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Interferon type III

2024-06-12T15:30:21Z

167.201.243.136: Italicized gene abbreviations

{{Short description|Group of anti-viral cytokines}}
{{Pfam box|Symbol=IL28A|Name=Interferon type III (λ)|InterPro=IPR029177|Pfam=PF15177|CATH=3og6A00}}The type '''III [[interferon]] group''' is a group of anti-viral cytokines, that consists of four IFN-λ (lambda) molecules called '''IFN-λ1''', '''IFN-λ2''', '''IFN-λ3''' (also known as IL29, IL28A and IL28B respectively), and '''IFN-λ4'''.<ref>{{cite journal | vauthors = Vilcek J | title = Novel interferons | journal = Nature Immunology | volume = 4 | issue = 1 | pages = 8–9 | date = January 2003 | pmid = 12496969 | doi = 10.1038/ni0103-8 | s2cid = 32338644 }}</ref> They were discovered in 2003.<ref name="Kotenko 69–77">{{cite journal | vauthors = Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, Langer JA, Sheikh F, Dickensheets H, Donnelly RP | display-authors = 6 | title = IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex | journal = Nature Immunology | volume = 4 | issue = 1 | pages = 69–77 | date = January 2003 | pmid = 12483210 | doi = 10.1038/ni875 | s2cid = 2734534 }}</ref> Their function is similar to that of type I interferons, but is less intense and serves mostly as a first-line defense against viruses in the epithelium.<ref name=":02">{{cite journal | vauthors = Kotenko SV, Durbin JE | title = Contribution of type III interferons to antiviral immunity: location, location, location | journal = The Journal of Biological Chemistry | volume = 292 | issue = 18 | pages = 7295–7303 | date = May 2017 | pmid = 28289095 | pmc = 5418032 | doi = 10.1074/jbc.R117.777102 | doi-access = free }}</ref>

== Genomic location ==
Genes encoding this group of interferons are all located on the long arm of chromosome 19 in human, specifically in region between 19q13.12 and 19q13.13. The ''IFNL1'' gene, encoding [[Interleukin 29|IL-29]], is located downstream of ''IFNL2'', encoding [[IL28A|IL-28A]]. ''IFNL3'', encoding [[IL28B]], is located downstream of IFNL4.<ref>{{cite journal | vauthors = Zhou JH, Wang YN, Chang QY, Ma P, Hu Y, Cao X | title = Type III Interferons in Viral Infection and Antiviral Immunity | language = english | journal = Cellular Physiology and Biochemistry | volume = 51 | issue = 1 | pages = 173–185 | date = 2018 | pmid = 30439714 | doi = 10.1159/000495172 | doi-access = free }}</ref><ref name=":3"/>

In mice, the genes encoding for type III interferons are located on chromosome 7 and the family consists only of IFN-λ2 and IFN-λ3.<ref name=":1">{{cite journal | vauthors = Lazear HM, Schoggins JW, Diamond MS | title = Shared and Distinct Functions of Type I and Type III Interferons | journal = Immunity | volume = 50 | issue = 4 | pages = 907–923 | date = April 2019 | pmid = 30995506 | pmc = 6839410 | doi = 10.1016/j.immuni.2019.03.025 }}</ref>
[[File:Interferon lambda genes.jpg|thumb|368x368px|Type III interferon (interferon lambda) genes on human chromosome 19]]

== Structure ==

=== Interferons ===
All interferon groups belong to class II cytokine family which have a conserved structure that comprises six [[Alpha helix|α-helices]].<ref name=":2">{{cite journal | vauthors = Renauld JC | title = Class II cytokine receptors and their ligands: key antiviral and inflammatory modulators | journal = Nature Reviews. Immunology | volume = 3 | issue = 8 | pages = 667–76 | date = August 2003 | pmid = 12974481 | doi = 10.1038/nri1153 | s2cid = 1229288 }}</ref> The proteins of type III interferon group are highly homologous and show high amino acid sequence similarity between. The similarity between IFN-λ2 and IFN-λ3 is approximately 96%, similarity of IFNλ1 to IFNλ 2/3 is around 81%.<ref name="Kotenko 69–77"/> Lowest similarity is found between IFN-λ4 and IFN-λ3 - only around 30%.<ref>{{cite journal | vauthors = O'Brien TR, Prokunina-Olsson L, Donnelly RP | title = IFN-λ4: the paradoxical new member of the interferon lambda family | journal = Journal of Interferon & Cytokine Research | volume = 34 | issue = 11 | pages = 829–38 | date = November 2014 | pmid = 24786669 | pmc = 4217005 | doi = 10.1089/jir.2013.0136 }}</ref><ref name="Fox e4933">{{cite journal | vauthors = Fox BA, Sheppard PO, O'Hara PJ | title = The role of genomic data in the discovery, annotation and evolutionary interpretation of the interferon-lambda family | journal = PLOS ONE | volume = 4 | issue = 3 | pages = e4933 | date = 2009-03-20 | pmid = 19300512 | pmc = 2654155 | doi = 10.1371/journal.pone.0004933 | bibcode = 2009PLoSO...4.4933F | doi-access = free }}</ref> Unlike type I interferon group, which consist of only one exon, type III interferons consist of multiple exons.<ref name=":1" /><ref name=":3">{{cite journal | vauthors = Syedbasha M, Egli A | title = Interferon Lambda: Modulating Immunity in Infectious Diseases | journal = Frontiers in Immunology | volume = 8 | pages = 119 | date = 2017-02-28 | pmid = 28293236 | pmc = 5328987 | doi = 10.3389/fimmu.2017.00119 | doi-access = free }}</ref>

=== Receptor ===
The receptors for these cytokines are also structurally conserved. The receptors have two type III [[fibronectin]] domains in their extracellular domain. The interface of these two domains forms the cytokine binding site.<ref name=":2" /> The receptor complex for type III interferons consists of two subunits - [[Interleukin 10 receptor, beta subunit|IL10RB]] (also called IL10R2 or CRF2-4) and [[IFNLR1]] (formerly called IL28RA, CRF2-12).<ref>{{cite journal | vauthors = Bartlett NW, Buttigieg K, Kotenko SV, Smith GL | title = Murine interferon lambdas (type III interferons) exhibit potent antiviral activity in vivo in a poxvirus infection model | journal = The Journal of General Virology | volume = 86 | issue = Pt 6 | pages = 1589–1596 | date = June 2005 | pmid = 15914836 | doi = 10.1099/vir.0.80904-0 | doi-access = free }}</ref>

In contrast to the ubiquitous expression of receptors for type I interferons, [[Interleukin 28 receptor, alpha subunit|IFNLR1]] is largely restricted to tissues of epithelial origin.<ref name="Kotenko 69–77"/><ref>{{cite journal | vauthors = Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, Kuestner R, Garrigues U, Birks C, Roraback J, Ostrander C, Dong D, Shin J, Presnell S, Fox B, Haldeman B, Cooper E, Taft D, Gilbert T, Grant FJ, Tackett M, Krivan W, McKnight G, Clegg C, Foster D, Klucher KM | display-authors = 6 | title = IL-28, IL-29 and their class II cytokine receptor IL-28R | journal = Nature Immunology | volume = 4 | issue = 1 | pages = 63–8 | date = January 2003 | pmid = 12469119 | doi = 10.1038/ni873 | s2cid = 35764259 }}</ref><ref name=":1" /> Despite high homology between type III interferons, the binding affinity to IFNLR1 differ, with IFN-λ1 showing the highest binding affinity, and IFN-λ3 showing the lowest binding affinity.<ref name="Fox e4933"/>

== Signalling pathway ==
IFN-λ production is induced by pathogen sensing through [[Pattern recognition receptor|pattern recognition receptors (PRR)]], including [[Toll-like receptor|TLR]], [[Ku70]] and [[RIG-I-like receptor|RIG-I-like]]. The main producer of IFN-λ are type 2 myeloid dendritic cells.<ref name=":3" />

IFN-λ binds to IFNLR1 with a high affinity, which then recruits the low-affinity subunit of the receptor, IL10Rb. This interaction creates a signalling complex.<ref name=":1" /> Upon binding of the cytokine to the receptor, [[JAK-STAT signaling pathway|JAK-STAT signalling pathway]] gets activated, specifically [[Janus kinase 1|JAK1]] and [[Tyrosine kinase 2|TYK2]] and phosphorylate and activate [[STAT1|STAT-1]] and [[STAT2|STAT-2]], which then induces downstream signalling that leads to induction of expression of hundreds of [[Interferon-stimulated gene|IFN-stimulated genes (ISG)]], e.g.: [[NF-κB]], [[Interferon regulatory factors|IRF]], ISRE, [[MX1|Mx1]], [[OAS1]].<ref name=":3" />

The signalling is modulated by [[Suppressor of cytokine signalling|suppressor of cytokine signalling 1]] (SOCS1) and ubiquitin-specific peptidase 18 (USP18).<ref name=":3" />

== Function ==
Functions of type III interferons overlap largely with that of [[Interferon type I|type I interferons]]. Both of these cytokine groups modulate the immune response after a pathogen has been sensed in the organism, their functions are mostly anti-viral and anti-proliferative. However, type III interferons tend to be less inflammatory and show a slower kinetics than type I. Also, because of the restricted expression of [[Interleukin 28 receptor, alpha subunit|IFNLR1]], the immunomodulatory effect of type III interferons is limited.<ref name=":1" /><ref name=":4">{{cite journal | vauthors = Wack A, Terczyńska-Dyla E, Hartmann R | title = Guarding the frontiers: the biology of type III interferons | journal = Nature Immunology | volume = 16 | issue = 8 | pages = 802–9 | date = August 2015 | pmid = 26194286 | pmc = 7096991 | doi = 10.1038/ni.3212 }}</ref>

Because the receptors for type I and type II interferons are expressed on almost all nucleated cells, their function is rather systemic. Type III interferon receptors are expressed more specifically on epithelial cells and some immune cells such as [[neutrophil]]s, and depending on the species, B cells and dendritic cells as well.<ref>{{Cite journal|last1=Broggi|first1=Achille|last2=Tan|first2=Yunhao|last3=Granucci|first3=Francesca|last4=Zanoni|first4=Ivan|date=October 2017|title=IFN-λ suppresses intestinal inflammation by non-translational regulation of neutrophil function|journal=Nature Immunology|volume=18|issue=10|pages=1084–1093|doi=10.1038/ni.3821|issn=1529-2916|pmc=5701513|pmid=28846084}}</ref><ref>{{cite journal | vauthors = Hemann EA, Green R, Turnbull JB, Langlois RA, Savan R, Gale M | title = Interferon-λ modulates dendritic cells to facilitate T cell immunity during infection with influenza A virus | journal = Nature Immunology | volume = 20 | issue = 8 | pages = 1035–1045 | date = August 2019 | pmid = 31235953 | doi = 10.1038/s41590-019-0408-z | pmc = 6642690 }}</ref><ref>{{cite journal | vauthors = Santer DM, Minty GE, Golec DP, Lu J, May J, Namdar A, Shah J, Elahi S, Proud D, Joyce M, Tyrrell DL, Houghton M | display-authors = 6 | title = Differential expression of interferon-lambda receptor 1 splice variants determines the magnitude of the antiviral response induced by interferon-lambda 3 in human immune cells | journal = PLOS Pathogens | volume = 16 | issue = 4 | pages = e1008515 | date = April 2020 | pmid = 32353085 | pmc = 7217487 | doi = 10.1371/journal.ppat.1008515 | doi-access = free }}</ref> Therefore, their antiviral effects are most prominent in barriers, in gastrointestinal, respiratory and reproductive tracts. Type III interferons usually act as the first line of defense against viruses at the barriers.<ref name=":02" /><ref>{{cite journal | vauthors = Lazear HM, Nice TJ, Diamond MS | title = Interferon-λ: Immune Functions at Barrier Surfaces and Beyond | journal = Immunity | volume = 43 | issue = 1 | pages = 15–28 | date = July 2015 | pmid = 26200010 | pmc = 4527169 | doi = 10.1016/j.immuni.2015.07.001 }}</ref>

In the gastrointestinal tract, both type I and type III interferons are needed to effectively fight [[reovirus]] infection. Type III interferons restrict the initial replication of the virus and diminish the shedding of through feces, while type I interferons prevent the systematic infection. On the other hand, in the respiratory tract these two groups of interferons seem to be rather redundant, as documented by the susceptibility of double-deficient mice (in receptors for type I and type III interferons), but the resistance to respiratory virus in mice that are deficient in either type I or type III interferon receptors.<ref name=":4" /> Additional gastrointestinal viruses such as rotavirus and norovirus, as well as non-gastrointestinal viruses like influenza and West Nile virus, are also restricted by type III interferons.<ref>{{cite journal | vauthors = Ingle H, Peterson ST, Baldridge MT | title = Distinct Effects of Type I and III Interferons on Enteric Viruses | journal = Viruses | volume = 10 | issue = 1 | date = January 2018 | page = 46 | pmid = 29361691 | pmc = 5795459 | doi = 10.3390/v10010046 | doi-access = free }}</ref>

== References ==
{{Reflist|2}}

{{Interferons}}

[[Category:Cytokines]]
[[Category:Antiviral drugs]]

Juvenile polyposis syndrome

2024-06-07T23:11:08Z

167.201.243.136: Moved synonym to juvenile polyp page (not a synonym of the genetic syndrome)

{{Infobox medical condition (new)
| name = Juvenile polyposis syndrome
| synonyms =
| image = Gastric juvenile polyp - very low mag.jpg
| caption = [[Micrograph]] of a gastric juvenile polyp, as may be seen in juvenile polyposis syndrome. [[H&E stain]]
| symptoms =
| complications =
| onset =
| duration =
| types =
| causes = [[Genetic mutation]] in ''[[BMPR1A]]'' or ''[[SMAD4]]''
| risks =
| diagnosis =
| differential =
| prevention =
| treatment =
| medication =
| prognosis =
| frequency =
| deaths =
}}
'''Juvenile polyposis syndrome''' is an [[autosomal dominant]] genetic condition characterized by the appearance of multiple [[juvenile polyps]] in the gastrointestinal tract. Polyps are abnormal growths arising from a [[mucous membrane]]. These usually begin appearing before age 20, but the term ''juvenile'' refers to the type of polyp (i.e. benign hamartoma, as opposed to adenoma for example), not to the age of the affected person.<ref name=NBK1469>{{harvnb|GeneReviews NBK1469}}</ref> While the majority of the polyps found in juvenile polyposis syndrome are non-[[neoplastic]], [[hamartomatous]], self-limiting and benign, there is an increased risk of [[Adenocarcinoma, colon|adenocarcinoma]].

Solitary juvenile polyps most commonly occur in the rectum and present with rectal bleeding. The [[World Health Organization]] criteria for diagnosis of juvenile polyposis syndrome are one of either:
# More than five juvenile polyps in the colon or rectum; or
# Juvenile polyps throughout the [[gastrointestinal tract]]; or
# Any number of juvenile polyps in a person with a family history of juvenile polyposis.<ref name="Sternberg">{{cite book |author=Stoler, Mark A. |author2=Mills, Stacey E. |author3=Carter, Darryl |author4=Joel K Greenson |author5=Reuter, Victor E. |title=Sternberg's Diagnostic Surgical Pathology |publisher=Lippincott Williams & Wilkins |location=Hagerstwon, MD |year=2009 |isbn=978-0-7817-7942-5 }}</ref>

== Signs and symptoms ==

Age of onset is variable. The term 'juvenile' in the title of juvenile polyposis syndrome refers to the histological type of the polyps rather than the age of onset.

Affected individuals may present with rectal bleeding, abdominal pain, diarrhea or anemia. Diagnosis is typically by way of [[endoscopy]] and [[cytology]].<ref>{{cite journal |last1=Mogere |first1=Edwin |last2=Mwaura |first2=Elijah |last3=Waithaka |first3=Mark |last4=Mutua |first4=Victor |last5=Mugao |first5=Maurice |last6=von Csefalvay |first6=Chris |last7=Mukamati |first7=Dennis |title=Juvenile polyposis syndrome: A case report |journal=Clinical Case Reports |date=3 January 2023 |volume=11 |issue=1 |page=e6798 |doi=10.1002/ccr3.6798|pmid=36619487 |pmc=9810833 }}</ref> On [[colonoscopy]] or [[sigmoidoscopy]] polyps that vary in shape or size are present. The polyps can be sessile or pedunculated hamartomatous polyps.<ref name=NBK1469/>

== Genetics ==
Juvenile polyposis syndrome can occur sporadically in families or be inherited in an [[Dominance (genetics)|autosomal dominant manner]].{{citation needed|date=September 2021}}

Two [[gene]]s containing mutations associated with juvenile polyposis syndrome are ''[[BMPR1A]]'' and ''[[SMAD4]]''.<ref name=NBK1469/> Gene testing may be useful when trying to ascertain which non-symptomatic family members may be at risk of developing polyps, however having a known familial mutation would be unlikely to change the course of treatment. A known mutation may also be of use for affected individuals when they decide to start a family as it allows them reproductive choices.{{citation needed|date=September 2021}}

While [[mutation]]s in the gene ''[[PTEN (gene)|PTEN]]'' were also thought to have caused juvenile polyposis syndrome, it is now thought that mutations in this gene cause a similar clinical picture to juvenile polyposis syndrome but are actually affected with [[Cowden syndrome]] or other phenotypes of the [[PTEN hamartoma tumor syndrome]].<ref>{{cite book |author1=James, William D. |author2=Berger, Timothy G. |title=Andrews' Diseases of the Skin: Clinical Dermatology |publisher=Saunders Elsevier |year=2006 |isbn=0-7216-2921-0 |display-authors=etal}}</ref>

Mutations in ''SMAD4'' may be additionally associated with concomitant [[hereditary hemorrhagic telangiectasia]].<ref name=NBK1469/>

== Screening ==
People with juvenile polyps may require yearly upper and lower [[endoscopies]] with polyp excision and [[cell biology|cytology]]. Their siblings may also need to be screened regularly.<ref name="Familial Juvenile Polyposis">{{cite web |url=https://www.lecturio.com/concepts/familial-juvenile-polyposis/| title=Familial Juvenile Polyposis
|website=The Lecturio Medical Concept Library |access-date= 22 July 2021}}</ref>

==Treatment==
[[Malignant]] transformation of polyps requires surgical [[colectomy]].<ref name="Familial Juvenile Polyposis"/>

== Prognosis ==
Most juvenile polyps are benign; however, [[malignancy]] can occur. The cumulative lifetime risk of colorectal cancer is 39% in patients with juvenile polyposis syndrome.<ref name=Brosens>{{cite journal|last=Brosens|first=Lodewijk|title=Juvenile polyposis syndrome|journal=World Journal of Gastroenterology|year=2011|volume=17|issue=44|pages=4839–4844|doi=10.3748/wjg.v17.i44.4839|pmc=3235625|pmid=22171123|display-authors=etal |doi-access=free }}</ref>

==References==
{{reflist}}

==Further reading==
* {{cite book |vauthors=Larsen Haidle J, MacFarland SP, Howe JR|chapter=Juvenile Polyposis Syndrome |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1469/ |date=February 3, 2022|id=NBK1469 |pmid=20301642|access-date=7 June 2024|via=National Library of Medicine|title=GeneReviews [Internet]|orig-date=Copyright 1993–2024|publisher=University of Washington, Seattle|location=Seattle, Washington|url=https://www.ncbi.nlm.nih.gov/books/n/gene/TOC/|ref={{harvid|GeneReviews NBK1469}}|display-editors=6|veditors=Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A}}

== External links ==
{{Medical resources
| DiseasesDB = 7067
| ICD10 =
| ICD9 =
| ICDO =
| OMIM = 174900
| MedlinePlus =
| eMedicineSubj =
| eMedicineTopic =
| MeshID =
| GeneReviewsNBK = NBK1469
| GeneReviewsName = Juvenile Polyposis Syndrome
}}

{{Digestive system neoplasia}}
{{Cell surface receptor deficiencies}}

[[Category:Cell surface receptor deficiencies]]
[[Category:Pediatric cancers]]
[[Category:Hereditary cancers]]
[[Category:Gastrointestinal cancer]]
[[Category:Syndromes affecting the gastrointestinal tract]]

SCNN1G

2024-06-06T14:46:04Z

167.201.243.136: Italicized gene abbreviations

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
The '''''SCNN1G''''' gene encodes for the γ subunit of the epithelial sodium channel [[ENaC]] in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by ''[[SCNN1A]]'', ''[[SCNN1B]]'', and ''[[SCNN1D]]''.<ref name="2016-Hanukoglu" >{{cite journal | vauthors = Hanukoglu I, Hanukoglu A | title = Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases. | journal = Gene | volume = 579 | issue = 2 | pages = 95–132 | date = Jan 2016 | pmid = 26772908 | doi = 10.1016/j.gene.2015.12.061 | pmc=4756657}}</ref>

ENaC is expressed in epithelial cells and is different from the voltage-gated sodium channel that is involved in the generation of action potentials in neurons. The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1) represents that these are NON-voltage-gated channels.

In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid.<ref>{{cite journal | vauthors = Bourque CW | title = Central mechanisms of osmosensation and systemic osmoregulation | journal = Nature Reviews. Neuroscience | volume = 9 | issue = 7 | pages = 519–31 | date = Jul 2008 | pmid = 18509340 | doi = 10.1038/nrn2400 | s2cid = 205504313 }}</ref> ENaC allows transfer of sodium ions across the epithelial cell membrane in so-called "tight-epithelia" that have low permeability. The flow of sodium ions across epithelia affects osmolarity of the extracellular fluid. Thus, ENaC plays a central role in the regulation of body fluid and electrolyte homeostasis and consequently affects blood pressure.<ref name="2015-Rossier">{{cite journal | vauthors = Rossier BC, Baker ME, Studer RA | title = Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited | journal = Physiological Reviews | volume = 95 | issue = 1 | pages = 297–340 | date = Jan 2015 | pmid = 25540145 | doi = 10.1152/physrev.00011.2014 }}</ref>

As ENaC is strongly inhibited by [[amiloride]], it is also referred to as an "amiloride-sensitive sodium channel".

== History ==

The first cDNA encoding the gamma subunit of ENaC was cloned and sequenced by Canessa et al. from rat mRNA.<ref>{{cite journal | vauthors = Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD, Rossier BC | title = Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.| journal = Nature | volume = 367 | issue = 6462 | pages = 463–7 | date = Feb 1994 | pmid = 8107805 | doi = 10.1038/367463a0 | bibcode = 1994Natur.367..463C| s2cid = 769822}}</ref> A year later, two independent groups reported the cDNA sequences of the beta- and gamma-subunits of the human ENaC.<ref>{{cite journal | vauthors = McDonald FJ, Price MP, Snyder PM, Welsh MJ | title = Cloning and expression of the beta- and gamma-subunits of the human epithelial sodium channel | journal = American Journal of Physiology | volume = 268 | issue = 5 Pt 1 |pages=C1157–63 | date = May 1995 | pmid = 7762608 | doi = 10.1152/ajpcell.1995.268.5.C1157 }}</ref><ref name = "1995-Voilley" >{{cite journal | vauthors = Voilley N, Bassilana F, Mignon C, Merscher S, Mattéi MG, Carle GF, Lazdunski M, Barbry P | title = Cloning, chromosomal localization, and physical linkage of the beta and gamma subunits (SCNN1B and SCNN1G) of the human epithelial amiloride-sensitive sodium channel |journal = Genomics | volume = 28 | issue = 3 | pages = 560–5 | date = Aug 1995 | pmid = 7490094 | doi = 10.1006/geno.1995.1188 }}</ref>
The complete coding sequence human γ subunit was reported by Saxena et al.<ref name = "2002-Saxena" >{{ cite journal | vauthors = Saxena A, Hanukoglu I, Saxena D, Thompson RJ, Gardiner RM, Hanukoglu A | title = Novel mutations responsible for autosomal recessive multisystem pseudohypoaldosteronism and sequence variants in epithelial sodium channel alpha-, beta-, and gamma-subunit genes | journal= Journal of Clinical Endocrinology and Metabolism | volume = 87 | issue = 7 | pages = 3344–50 | date = Jul 2002 | pmid = 12107247 | doi= 10.1210/jcem.87.7.8674 | doi-access = free }}</ref>

== Gene structure ==

While the human gene [[SCNN1A]] is located in chromosome 12p,<ref name="1998-Ludwig">{{cite journal | vauthors = Ludwig M, Bolkenius U, Wickert L, Marynen P, Bidlingmaier F | title = Structural organisation of the gene encoding the alpha-subunit of the human amiloride-sensitive epithelial sodium channel | journal = Human Genetics | volume = 102 | issue = 5 | pages = 576–81 | date = May 1998 | pmid = 9654208 | doi=10.1007/s004390050743| s2cid = 22547152 }}</ref> the human genes encoding SCNN1B and SCNN1G are located in juxtoposition in the short arm of chromosome 16 (16p12-p13).<ref name = "1995-Voilley" /> The structures of the human and rat SCNN1G genes were first reported by Thomas et al.<ref>{{cite journal| vauthors = Thomas CP, Doggett NA, Fisher R, Stokes JB | title = Genomic organization and the 5' flanking region of the gamma subunit of the human amiloride-sensitive epithelial sodium channel | journal = Journal of Biological Chemistry | volume = 271 | issue = 42 |pages = 26062–6 |date = Oct 1996 | pmid = 8824247 | doi=10.1074/jbc.271.42.26062| doi-access = free }}</ref><ref>{{ cite journal | vauthors = Thomas CP, Auerbach SD, Zhang C, Stokes JB | title = The structure of the rat amiloride-sensitive epithelial sodium channel gamma subunit gene and functional analysis of its promoter | journal = Gene | volume = 228 | issue = 1–2 | pages = 111–22 | date = Mar 1999 | pmid=10072764 | doi=10.1016/s0378-1119(99)00016-5}}</ref> Later studies by Saxena et al. reported the complete coding sequence of the human SCNN1G gene establishing that it has 13 exons <ref name = "2002-Saxena" /> The positions of introns are conserved in all three human ENaC genes, SCNN1A, SCNN1B and SCNN1G.<ref name = "1998-Saxena" >{{cite journal | vauthors = Saxena A, Hanukoglu I, Strautnieks SS, Thompson RJ, Gardiner RM, Hanukoglu A | title = Gene structure of the human amiloride-sensitive epithelial sodium channel beta subunit | journal = Biochemical and Biophysical Research Communications | volume = 252 | issue = 1 | pages = 208–213 | date = Nov 1998 | pmid=9813171 | doi = 10.1006/bbrc.1998.9625}}</ref> The positions of the introns are also highly conserved across vertebrates See: [http://www.ensembl.org/Homo_sapiens/Gene/Compara_Tree?db=core;g=ENSG00000168447;r=16:23278231-23381299 Ensembl GeneTree].

[[File:SCNN1G-gene-transcript-Hanukoglu.png|framed|left|link=http://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000166828;r=16:23182715-23216883;t=ENST00000300061 |Fig. 1. Exon-intron structure of the major transcript of the human SCNN1B. The number of each exon is marked above the exon. The serial number of the transcript is shown above the transcript. Clicking on the figure will direct the reader to the list of transcripts in the Ensembl database.]]
{{clear}}

== Tissue-specific expression ==

The three ENaC subunits encoded by [[SCNN1A]], SCNN1B, and SCNN1G are commonly expressed in tight epithelia that have low water permeability. The major organs where ENaC is expressed include parts of the kidney tubular epithelia,<ref name="2016-Hanukoglu" /><ref name="2015-Rossier" /><ref name="1994-Duc">{{cite journal | vauthors = Duc C, Farman N, Canessa CM, Bonvalet JP, Rossier BC | title = Cell-specific expression of epithelial sodium channel alpha, beta, and gamma subunits in aldosterone-responsive epithelia from the rat: localization by in situ hybridization and immunocytochemistry | journal = The Journal of Cell Biology | volume = 127 | issue = 6 Pt 2 | pages = 1907–21 | date = Dec 1994 | pmid = 7806569 | pmc=2120291 | doi=10.1083/jcb.127.6.1907}}</ref> the respiratory airway,<ref name="2012-Enuka">{{cite journal | vauthors = Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A | title = Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways | journal = Histochemistry and Cell Biology | volume = 137 | issue = 3 | pages = 339–53 | date = Mar 2012 | pmid = 22207244 | doi = 10.1007/s00418-011-0904-1 | s2cid = 15178940 }}</ref> the female reproductive tract,<ref name="2012-Enuka" /> colon, salivary and sweat glands.<ref name="1994-Duc" />

ENaC is also expressed in the tongue, where it has been shown to be essential for the perception of salt taste.<ref name="1994-Duc"/>

The expression of ENaC subunit genes is regulated mainly by the mineralocorticoid hormone aldosterone that is activated by the renin-angiotensin system.<ref>{{cite journal | vauthors = Palmer LG, Patel A, Frindt G | title = Regulation and dysregulation of epithelial Na+ channels | journal = Clinical and Experimental Nephrology | volume = 16 | issue = 1 | pages = 35–43 | date = Feb 2012 | pmid = 22038262 | doi = 10.1007/s10157-011-0496-z | s2cid = 19437696 }}</ref><ref>{{cite journal | vauthors = Thomas W, Harvey BJ | title = Mechanisms underlying rapid aldosterone effects in the kidney | journal = Annual Review of Physiology | volume = 73 | pages = 335–57 | date = 2011 | pmid = 20809792 | doi = 10.1146/annurev-physiol-012110-142222 | url = https://epubs.rcsi.ie/cgi/viewcontent.cgi?article=1006&context=molmedart }}</ref>

== Protein structure ==

The primary structures of all four ENaC subunits show strong similarity. Thus, these four proteins represent a family of proteins that share a common ancestor. In global alignment (meaning alignments of sequences along their entire length and not just a partial segment), the human γ subunit shares 34% identity with the β subunit and 27 and 23% identity with the α and δ subunits.

All four ENaC subunit sequences have two hydrophobic stretches that form two transmembrane segments named as TM1 and TM2.<ref name="2016-Hanukoglu" /><ref>{{cite journal | vauthors = Canessa CM, Merillat AM, Rossier BC | title = Membrane topology of the epithelial sodium channel in intact cells | journal = The American Journal of Physiology | volume = 267 | issue = 6 Pt 1 | pages = C1682–90 | date = Dec 1994 | pmid = 7810611 | doi = 10.1152/ajpcell.1994.267.6.C1682 }}</ref>
In the membrane-bound form, the TM segments are embedded in the membrane bilayer, the amino- and carboxy-terminal regions are located inside the cell, and the segment between the two TMs remains outside of the cell as the extracellular region of ENaC. This extracellular region includes about 70% of the residues of each subunit. Thus, in the membrane-bound form, the bulk of each subunit is located outside of the cell.<ref name="2016-Hanukoglu" />

The structure of ENaC has not been yet determined. Yet, the structure of a homologous protein ASIC1 has been resolved.<ref name="2007-Jasti">{{cite journal | vauthors = Jasti J, Furukawa H, Gonzales EB, Gouaux E | title = Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH | journal = Nature | volume = 449 | issue = 7160 | pages = 316–23 | date = Sep 2007 | pmid = 17882215 | doi = 10.1038/nature06163 | bibcode = 2007Natur.449..316J }}</ref><ref>{{cite journal | vauthors = Baconguis I, Bohlen CJ, Goehring A, Julius D, Gouaux E | title = X-ray structure of acid-sensing ion channel 1-snake toxin complex reveals open state of a Na(+)-selective channel | journal = Cell | volume = 156 | issue = 4 | pages = 717–29 | date = Feb 2014 | pmid = 24507937 | doi = 10.1016/j.cell.2014.01.011 | pmc=4190031}}</ref> The chicken ASIC1 structure revealed that ASIC1 is assembled as a homotrimer of three identical subunits. The authors of the original study suggested that the ASIC1 trimer resembles a hand holding a ball.<ref name="2007-Jasti" /> Hence distinct domains of ASIC1 have been referred to as palm, knuckle, finger, thumb, and β-ball.<ref name="2007-Jasti" />

Site-directed mutagenesis of the human γ subunit suggests that ENaC subunits have a structure similar to that of ASIC1.<ref name="2014-Edelheit">{{cite journal | vauthors = Edelheit O, Ben-Shahar R, Dascal N, Hanukoglu A, Hanukoglu I | title = Conserved charged residues at the surface and interface of epithelial sodium channel (ENaC) subunits: roles in cell surface expression and Na+ self-inhibition response | journal = FEBS Journal | volume = 281 | issue = 8 | pages = 2097–2111 | date = Apr 2014 | pmid = 24571549 | doi = 10.1111/febs.12765 | s2cid = 5807500 | doi-access = free }}</ref> The ion selectivity filter of ENaC has been modeled based on the ASIC1 structure.<ref name="2016-Hanukoglu-b" >{{cite journal | vauthors = Hanukoglu I | title = ASIC and ENaC type sodium channels: Conformational states and the structures of the ion selectivity filters | journal = FEBS Journal | volume = 284 | issue= 4 | pages= 525–545 | year= 2017 | pmid= 27580245 | doi= 10.1111/febs.13840 | s2cid = 24402104 | url=https://zenodo.org/record/890906}}</ref>

Alignment of ENaC subunit sequences with ASIC1 sequence reveals that TM1 and TM2 segments and palm domain are conserved, and the knuckle, finger and thumb domains have insertions in ENaC. Site-directed mutagenesis studies on ENaC subunits provide evidence that many basic features of the ASIC1 structural model apply to ENaC as well.<ref name="2016-Hanukoglu" />

In the carboxy terminus of three ENaC subunits, (α, β and γ) there is a special conserved consensus sequence PPPXYXXL that is called the PY motif. This sequence is recognized by the so-called WW domains in a special E3 ubiquitin-protein ligase named Nedd4-2.<ref name = "2011-Rotin" >{{cite journal | vauthors = Rotin D, Staub O|title = Role of the ubiquitin system in regulating ion transport | journal = Pflügers Archiv: European Journal of Physiology | volume = 461 | issue = 1 |pages = 1–21 | date = Jan 2011 | pmid=20972579 | doi = 10.1007/s00424-010-0893-2|s2cid = 23272309 | url = http://doc.rero.ch/record/310765/files/424_2010_Article_893.pdf }}</ref> Nedd4-2 ligates [[ubiquitin]] to the C-terminus of the ENaC subunit which marks the protein for degradation.<ref name = "2011-Rotin" />

== Associated diseases ==
At present, three major hereditary disorders are known to be associated with mutations in the SCNN1G gene. These are:
1. Multisystem pseudohypoaldosteronism, 2. Liddle syndrome, and 3. Cystic fibrosis-like disease.<ref name="2016-Hanukoglu" />

===Multi-system form of type I pseudohypoaldosteronism (PHA1B)===
The disease most commonly associated with mutations in SCNN1B is the multi-system form of type I pseudohypoaldosteronism (PHA1B) that was first characterized by A. Hanukoglu as an autosomal recessive disease.<ref>{{cite journal | vauthors = Hanukoglu A | title = Type I pseudohypoaldosteronism includes two clinically and genetically distinct entities with either renal or multiple target organ defects | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 73 | issue = 5 | pages = 936–44 | date = Nov 1991 | pmid = 1939532 | doi = 10.1210/jcem-73-5-936 | url = https://zenodo.org/record/890914 }}</ref> This is a syndrome of unresponsiveness to aldosterone in patients that have high serum levels of aldosterone but suffer from symptoms of aldosterone deficiency with a high risk of mortality due to severe salt loss. Initially, this disease was thought to be a result of a mutation in the mineralocorticoid receptor (NR3C2) that binds aldosterone. But homozygosity mapping in 11 affected families revealed that the disease is associated with two loci on chromosome 12p13.1-pter and chromosome 16p12.2-13 that include the genes for SCNN1A and SCNN1B and SCNN1G respectively.<ref>{{cite journal | vauthors = Strautnieks SS, Thompson RJ, Hanukoglu A, Dillon MJ, Hanukoglu I, Kuhnle U, Seckl J, Gardiner RM, Chung E | title = Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping | journal = Human Molecular Genetics | volume = 5 | issue = 2 | pages = 293–9 | date = Feb 1996 | pmid = 8824886 | doi=10.1093/hmg/5.2.293| doi-access = }}</ref> Sequencing of the ENaC genes identified mutation in affected patients, and functional expression of the mutated cDNAs further confirmed that identified mutations lead to the loss of activity of ENaC.<ref>{{cite journal | vauthors = Chang SS, Grunder S, Hanukoglu A, Rösler A, Mathew PM, Hanukoglu I, Schild L, Lu Y, Shimkets RA, Nelson-Williams C, Rossier BC, Lifton RP | title = Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1 | journal = Nature Genetics | volume = 12 | issue = 3 | pages = 248–53 | date = Mar 1996 | pmid = 8589714 | doi = 10.1038/ng0396-248 | s2cid = 8185511 }}</ref>

In the majority of the patients with multi-system PHA1B a homozygous mutation or two compound heterozygous mutations have been detected.<ref>{{cite journal | vauthors = Strautnieks SS, Thompson RJ, Gardiner RM, Chung E | title = A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families | journal = Nature Genetics | volume = 13 | issue = 2 | pages = 248–50 | date = Jun 1996 | pmid = 8640238 | doi = 10.1038/ng0696-248 | s2cid = 21124946 }}</ref><ref>{{cite journal | vauthors = Edelheit O, Hanukoglu I, Gizewska M, Kandemir N, Tenenbaum-Rakover Y, Yurdakök M, Zajaczek S, Hanukoglu A | title = Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism | journal = Clinical Endocrinology | volume = 62 | issue = 5 | pages = 547–53 | date = May 2005 | pmid = 15853823 | doi = 10.1111/j.1365-2265.2005.02255.x | s2cid = 2749562 }}</ref><ref>{{cite journal | vauthors = Zennaro MC, Hubert EL, Fernandes-Rosa FL | title = Aldosterone resistance: structural and functional considerations and new perspectives | journal = Molecular and Cellular Endocrinology | volume = 350 | issue = 2 | pages = 206–15 | date = Mar 2012 | pmid = 21664233 | doi = 10.1016/j.mce.2011.04.023 | s2cid = 24896754 }}</ref>

===Liddle syndrome===

Liddle syndrome is generally caused by mutations in the PY motif or truncation of the C-terminus including loss of the PY motif in the β or γ ENaC subunits.<ref>{{cite journal | vauthors = Hansson JH, Nelson-Williams C, Suzuki H, Schild L, Shimkets R, Lu Y, Canessa C, Iwasaki T, Rossier B, Lifton RP | title = Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome | journal = Nat. Genet. | volume = 11 | issue = 1 | pages = 76–82 | year = 1995 | pmid = 7550319 | doi = 10.1038/ng0995-76 | s2cid = 22106822 }}</ref><ref>{{cite journal | vauthors = Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, Gill JR, Ulick S, Milora RV, Findling JW | title = Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel | journal = Cell | volume = 79 | issue = 3 | pages = 407–14 | year = 1994 | pmid = 7954808 | doi = 10.1016/0092-8674(94)90250-X | s2cid = 54282654 }}</ref><ref>{{cite journal | vauthors = Hansson JH, Schild L, Lu Y, Wilson TA, Gautschi I, Shimkets R, Nelson-Williams C, Rossier BC, Lifton RP | title = A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 92 | issue = 25 | pages = 11495–9 | year = 1996 | pmid = 8524790 | pmc = 40428 | doi = 10.1073/pnas.92.25.11495 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Inoue J, Iwaoka T, Tokunaga H, Takamune K, Naomi S, Araki M, Takahama K, Yamaguchi K, Tomita K | title = A family with Liddle's syndrome caused by a new missense mutation in the beta subunit of the epithelial sodium channel | journal = J. Clin. Endocrinol. Metab. | volume = 83 | issue = 6 | pages = 2210–3 | year = 1998 | doi = 10.1210/jcem.83.6.5030 | pmid = 9626162 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Persu A, Barbry P, Bassilana F, Houot AM, Mengual R, Lazdunski M, Corvol P, Jeunemaitre X | title = Genetic analysis of the beta subunit of the epithelial Na+ channel in essential hypertension | journal = Hypertension | volume = 32 | issue = 1 | pages = 129–37 | year = 1998 | pmid = 9674649 | doi = 10.1161/01.hyp.32.1.129 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Uehara Y, Sasaguri M, Kinoshita A, Tsuji E, Kiyose H, Taniguchi H, Noda K, Ideishi M, Inoue J, Tomita K, Arakawa K | title = Genetic analysis of the epithelial sodium channel in Liddle's syndrome | journal = J. Hypertens. | volume = 16 | issue = 8 | pages = 1131–5 | year = 1998 | pmid = 9794716 | doi = 10.1097/00004872-199816080-00008 | s2cid = 31393115 }}</ref> Even though there is a PY motif also in the α subunit, so far Liddle disease has not observed in association with a mutation in the α subunit. Liddle syndrome is inherited as an autosomal dominant disease with a phenotype that includes early onset hypertension, metabolic alkalosis and low levels of plasma renin activity and mineralocorticoid hormone aldosterone. In the absence of a recognizable PY motif, ubiquitin-protein ligase Nedd4-2 cannot bind to the ENaC subunit and hence cannot attach a ubiquitin to it. Consequently, proteolysis of ENaC by proteasome is inhibited and ENaC accumulates in the membrane leading to enhanced activity of ENaC that causes hypertension.<ref>{{cite journal | vauthors = Snyder PM, Price MP, McDonald FJ, Adams CM, Volk KA, Zeiher BG, Stokes JB, Welsh MJ | title = Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel | journal = Cell | volume = 83 | issue = 6 | pages = 969–78 | year = 1996 | pmid = 8521520 | doi = 10.1016/0092-8674(95)90212-0 | s2cid = 970556 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Tamura H, Schild L, Enomoto N, Matsui N, Marumo F, Rossier BC | title = Liddle disease caused by a missense mutation of beta subunit of the epithelial sodium channel gene | journal = J. Clin. Invest. | volume = 97 | issue = 7 | pages = 1780–4 | year = 1996 | pmid = 8601645 | pmc = 507244 | doi = 10.1172/JCI118606 }}</ref><ref>{{cite journal | vauthors = Firsov D, Schild L, Gautschi I, Mérillat AM, Schneeberger E, Rossier BC | title = Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: A quantitative approach | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 93 | issue = 26 | pages = 15370–5 | year = 1997 | pmid = 8986818 | pmc = 26411 | doi = 10.1073/pnas.93.26.15370 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Pirozzi G, McConnell SJ, Uveges AJ, Carter JM, Sparks AB, Kay BK, Fowlkes DM | title = Identification of novel human WW domain-containing proteins by cloning of ligand targets | journal = J. Biol. Chem. | volume = 272 | issue = 23 | pages = 14611–6 | year = 1997 | pmid = 9169421 | doi = 10.1074/jbc.272.23.14611 | doi-access = free }}</ref>

== Interactions ==

SCNN1G has been shown to [[Protein-protein interaction|interact]] with:
* [[NEDD4]],<ref name = pmid10642508>{{cite journal | vauthors = Farr TJ, Coddington-Lawson SJ, Snyder PM, McDonald FJ | title = Human Nedd4 interacts with the human epithelial Na+ channel: WW3 but not WW1 binds to Na+-channel subunits | journal = Biochem. J. | volume = 345 | issue = 3| pages = 503–9 | date = February 2000 | pmid = 10642508 | pmc = 1220784 | doi = 10.1042/0264-6021:3450503}}</ref><ref name = pmid12167593>{{cite journal | vauthors = McDonald FJ, Western AH, McNeil JD, Thomas BC, Olson DR, Snyder PM | title = Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel | journal = Am. J. Physiol. Renal Physiol. | volume = 283 | issue = 3 | pages = F431–6 | date = September 2002 | pmid = 12167593 | doi = 10.1152/ajprenal.00080.2002 }}</ref><ref name = pmid11244092>{{cite journal | vauthors = Harvey KF, Dinudom A, Cook DI, Kumar S | title = The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel | journal = J. Biol. Chem. | volume = 276 | issue = 11 | pages = 8597–601 | date = March 2001 | pmid = 11244092 | doi = 10.1074/jbc.C000906200 | doi-access = free }}</ref>
* [[STX1A]],<ref name = pmid14996668>{{cite journal | vauthors = Berdiev BK, Jovov B, Tucker WC, Naren AP, Fuller CM, Chapman ER, Benos DJ | title = ENaC subunit-subunit interactions and inhibition by syntaxin 1A | journal = Am. J. Physiol. Renal Physiol. | volume = 286 | issue = 6 | pages = F1100–6 | date = June 2004 | pmid = 14996668 | doi = 10.1152/ajprenal.00344.2003 | s2cid = 18384316 }}</ref> and
* [[Ubiquitin C]]<ref name = pmid18632802>{{cite journal | vauthors = Boulkroun S, Ruffieux-Daidié D, Vitagliano JJ, Poirot O, Charles RP, Lagnaz D, Firsov D, Kellenberger S, Staub O | title = Vasopressin-inducible ubiquitin-specific protease 10 increases ENaC cell surface expression by deubiquitylating and stabilizing sorting nexin 3 | journal = Am. J. Physiol. Renal Physiol. | volume = 295 | issue = 4 | pages = F889–900 | date = October 2008 | pmid = 18632802 | doi = 10.1152/ajprenal.00001.2008 }}</ref><ref name = pmid18322022>{{cite journal | vauthors = Raikwar NS, Thomas CP | title = Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel | journal = Am. J. Physiol. Renal Physiol. | volume = 294 | issue = 5 | pages = F1157–65 | date = May 2008 | pmid = 18322022 | pmc = 2424110 | doi = 10.1152/ajprenal.00339.2007 }}</ref>

== See also ==
* [[Epithelial sodium channel]]

==Notes==
{{Academic-written review|Q=Q28272095}}

== References ==
{{Reflist|33em}}

== Further reading ==
{{Refbegin|33em}}

* {{cite journal | vauthors = Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover A, Schild L, Rotin D | title = Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination | journal = EMBO J. | volume = 16 | issue = 21 | pages = 6325–36 | year = 1998 | pmid = 9351815 | pmc = 1170239 | doi = 10.1093/emboj/16.21.6325 }}
* {{cite journal | vauthors = Arai K, Zachman K, Shibasaki T, Chrousos GP | title = Polymorphisms of amiloride-sensitive sodium channel subunits in five sporadic cases of pseudohypoaldosteronism: do they have pathologic potential? | journal = J. Clin. Endocrinol. Metab. | volume = 84 | issue = 7 | pages = 2434–7 | year = 1999 | doi = 10.1210/jcem.84.7.5857 | pmid = 10404817 | doi-access = free }}
* {{cite journal | vauthors = Auerbach SD, Loftus RW, Itani OA, Thomas CP | title = Human amiloride-sensitive epithelial Na+ channel gamma subunit promoter: functional analysis and identification of a polypurine-polypyrimidine tract with the potential for triplex DNA formation | journal = Biochem. J. | volume = 347 | issue = 1 | pages = 105–14 | year = 2000 | pmid = 10727408 | pmc = 1220937 | doi = 10.1042/0264-6021:3470105 }}
* {{cite journal | vauthors = Shi H, Asher C, Chigaev A, Yung Y, Reuveny E, Seger R, Garty H | title = Interactions of beta and gamma ENaC with Nedd4 can be facilitated by an ERK-mediated phosphorylation | journal = J. Biol. Chem. | volume = 277 | issue = 16 | pages = 13539–47 | year = 2002 | pmid = 11805112 | doi = 10.1074/jbc.M111717200 | doi-access = free }}
{{Refend}}

== External links ==
* {{MeshName|SCNN1G+protein,+human}}

{{Ion channels|g2}}

[[Category:Sodium channels]]

SCNN1B

2024-06-06T14:44:57Z

167.201.243.136: Italicized gene abbreviations

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{cs1 config|name-list-style=vanc}}
{{Infobox_gene}}
The '''''SCNN1B''''' gene encodes for the β subunit of the epithelial sodium channel [[ENaC]] in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by ''[[SCNN1A]]'', ''[[SCNN1G]]'', and ''[[SCNN1D]]''.<ref name="2016-Hanukoglu" >{{cite journal | vauthors = Hanukoglu I, Hanukoglu A | title = Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases. | journal = Gene | volume = 579 | issue = 2 | pages = 95–132 | date = Jan 2016 | pmid = 26772908 | doi = 10.1016/j.gene.2015.12.061 | pmc=4756657}}</ref>

ENaC is expressed in epithelial cells<ref name="2016-Hanukoglu" /> and is different from the voltage-gated sodium channel that is involved in the generation of action potentials in neurons. The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1A) represents that these are NON-voltage-gated channels.

In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid.<ref>{{cite journal | vauthors = Bourque CW | title = Central mechanisms of osmosensation and systemic osmoregulation | journal = Nature Reviews. Neuroscience | volume = 9 | issue = 7 | pages = 519–31 | date = Jul 2008 | pmid = 18509340 | doi = 10.1038/nrn2400 | s2cid = 205504313 }}</ref> ENaC allows transfer of sodium ions across the epithelial cell membrane in so-called "tight-epithelia" that have low permeability. The flow of sodium ions across epithelia affects osmolarity of the extracellular fluid. Thus, ENaC plays a central role in the regulation of body fluid and electrolyte homeostasis and consequently affects blood pressure.<ref name="2015-Rossier">{{cite journal | vauthors = Rossier BC, Baker ME, Studer RA | title = Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited | journal = Physiological Reviews | volume = 95 | issue = 1 | pages = 297–340 | date = Jan 2015 | pmid = 25540145 | doi = 10.1152/physrev.00011.2014 }}</ref>

As ENaC is strongly inhibited by [[amiloride]], it is also referred to as an "amiloride-sensitive sodium channel".

== History ==

The first cDNA encoding the beta subunit of ENaC was cloned and sequenced by Canessa et al. from rat mRNA.<ref>{{cite journal | vauthors = Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD, Rossier BC | title = Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.| journal = Nature | volume = 367 | issue = 6462 | pages = 463–7 | date = Feb 1994 | pmid = 8107805 | doi = 10.1038/367463a0 | bibcode = 1994Natur.367..463C| s2cid = 769822}}</ref> A year later, two independent groups reported the cDNA sequences of the beta- and gamma-subunits of the human ENaC.<ref>{{cite journal | vauthors = McDonald FJ, Price MP, Snyder PM, Welsh MJ | title = Cloning and expression of the beta- and gamma-subunits of the human epithelial sodium channel | journal = American Journal of Physiology | volume = 268 | issue = 5 Pt 1 |pages=C1157–63 | date = May 1995 | pmid = 7762608 | doi = 10.1152/ajpcell.1995.268.5.C1157 }}</ref><ref name = "1995-Voilley" >{{cite journal | vauthors = Voilley N, Bassilana F, Mignon C, Merscher S, Mattéi MG, Carle GF, Lazdunski M, Barbry P | title = Cloning, chromosomal localization, and physical linkage of the beta and gamma subunits (SCNN1B and SCNN1G) of the human epithelial amiloride-sensitive sodium channel |journal = Genomics | volume = 28 | issue = 3 | pages = 560–5 | date = Aug 1995 | pmid = 7490094 | doi = 10.1006/geno.1995.1188 }}</ref> The exon-intron organization of the human beta ENaC gene SCNN1B was determined by Saxena et al. by sequencing genomic DNA from three subjects from three different ethnic groups.<ref name = "1998-Saxena" >{{cite journal| vauthors = Saxena A, Hanukoglu I, Strautnieks SS, Thompson RJ, Gardiner RM, Hanukoglu A | title = Gene structure of the human amiloride-sensitive epithelial sodium channel beta subunit | journal = Biochemical and Biophysical Research Communications | volume = 252 | issue = 1 | pages = 208–13 | date = Nov 1998 | pmid=9813171 | doi = 10.1006/bbrc.1998.9625}}</ref> This study also established that the exon-intron architecture of the three subunits of ENaC have remained highly conserved despite the divergence of their sequences.<ref name = "1998-Saxena" />

== Gene structure ==

While the human gene [[SCNN1A]] is located in chromosome 12p,<ref name="1998-Ludwig">{{cite journal | vauthors = Ludwig M, Bolkenius U, Wickert L, Marynen P, Bidlingmaier F | title = Structural organisation of the gene encoding the alpha-subunit of the human amiloride-sensitive epithelial sodium channel | journal = Human Genetics | volume = 102 | issue = 5 | pages = 576–81 | date = May 1998 | pmid = 9654208 | doi=10.1007/s004390050743| s2cid = 22547152 }}</ref> the human genes encoding SCNN1B and SCNN1G are located in juxtaposition in the short arm of chromosome 16 (16p12-p13).<ref name = "1995-Voilley" /> Sequencing of the human genomic DNA indicated that the SCNN1B gene has 13 exons separated by 12 introns.<ref name = "1998-Saxena" /> The positions of introns are conserved in all three human ENaC genes, SCNN1A, SCNN1B and SCNN1G.<ref name = "1998-Saxena" /> The positions of the introns are also highly conserved across vertebrates. See: [http://www.ensembl.org/Homo_sapiens/Gene/Compara_Tree?db=core;g=ENSG00000168447;r=16:23278231-23381299 Ensembl GeneTree].

Analysis of transcripts of the SCNN1B gene in human kidney and lung showed several alternative transcription and translation initiation sites.<ref name = "2002-Thomas" >{{cite journal | vauthors = Thomas CP, Loftus RW, Liu KZ, Itani OA | title = Genomic organization of the 5' end of human beta-ENaC and preliminary characterization of its promoter | journal = American Journal of Physiology. Renal Physiology | volume = 282 | issue = 5 | pages = F898–909 | date = May 2002 | pmid=11934701 | doi=10.1152/ajprenal.00268.2001| s2cid = 2650201 }}</ref> However, only one of these transcripts (ENST00000343070) is highly expressed and other transcripts appear at low amounts.<ref name = "2002-Thomas" />

[[File:SCNN1B-gene-transcript-Hanukoglu.png|framed|left|link=http://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000168447;r=16:23278231-23381299|Fig. 1. Exon-intron structure of the major transcript of the human SCNN1B. The number of each exon is marked above the exon. The serial number of the transcript is shown above the transcript. Clicking on the figure will direct the reader to the list of transcripts in the Ensembl database.]]
{{clear}}

== Tissue-specific expression ==

The three ENaC subunits encoded by [[SCNN1A]], SCNN1B, and [[SCNN1G]] are commonly expressed in tight epithelia that have low water permeability.<ref name="2016-Hanukoglu" /> The major organs where ENaC is expressed include parts of the kidney tubular epithelia,<ref name="2015-Rossier" /><ref name="1994-Duc">{{cite journal | vauthors = Duc C, Farman N, Canessa CM, Bonvalet JP, Rossier BC | title = Cell-specific expression of epithelial sodium channel alpha, beta, and gamma subunits in aldosterone-responsive epithelia from the rat: localization by in situ hybridization and immunocytochemistry | journal = The Journal of Cell Biology | volume = 127 | issue = 6 Pt 2 | pages = 1907–21 | date = Dec 1994 | pmid = 7806569 | pmc=2120291 | doi=10.1083/jcb.127.6.1907}}</ref> the respiratory airway,<ref name="2012-Enuka">{{cite journal | vauthors = Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A | title = Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways | journal = Histochemistry and Cell Biology | volume = 137 | issue = 3 | pages = 339–53 | date = Mar 2012 | pmid = 22207244 | doi = 10.1007/s00418-011-0904-1 | s2cid = 15178940 }}</ref> the female reproductive tract,<ref name="2012-Enuka" /> colon, salivary and sweat glands.<ref name="1994-Duc" />

ENaC is also expressed in the tongue, where it has been shown to be essential for the perception of salt taste.<ref name="1994-Duc"/>

The expression of ENaC subunit genes is regulated mainly by the mineralocorticoid hormone aldosterone that is activated by the renin-angiotensin system.<ref>{{cite journal | vauthors = Palmer LG, Patel A, Frindt G | title = Regulation and dysregulation of epithelial Na+ channels | journal = Clinical and Experimental Nephrology | volume = 16 | issue = 1 | pages = 35–43 | date = Feb 2012 | pmid = 22038262 | doi = 10.1007/s10157-011-0496-z | s2cid = 19437696 }}</ref>
<ref>{{cite journal | vauthors = Thomas W, Harvey BJ | title = Mechanisms underlying rapid aldosterone effects in the kidney | journal = Annual Review of Physiology | volume = 73 | pages = 335–57 | date = 2011 | pmid = 20809792 | doi = 10.1146/annurev-physiol-012110-142222 | url = https://figshare.com/articles/journal_contribution/Mechanisms_Underlying_Rapid_Aldosterone_Effects_in_the_Kidney/10786559/3/files/19299440.pdf }}</ref>

== Protein structure ==

The primary structures of all four ENaC subunits show strong similarity. Thus, these four proteins represent a family of proteins that share a common ancestor. In global alignment (meaning alignments of sequences along their entire length and not just a partial segment), the human β subunit shares 34% identity with the γ subunit and 26 and 23% identity with the α and δ subunits.<ref name="2016-Hanukoglu" />

All four ENaC subunit sequences have two hydrophobic stretches that form two transmembrane segments named as TM1 and TM2.<ref>{{cite journal | vauthors = Canessa CM, Merillat AM, Rossier BC | title = Membrane topology of the epithelial sodium channel in intact cells | journal = The American Journal of Physiology | volume = 267 | issue = 6 Pt 1 | pages = C1682–90 | date = Dec 1994 | pmid = 7810611 | doi = 10.1152/ajpcell.1994.267.6.C1682 }}</ref>
In the membrane-bound form, the TM segments are embedded in the membrane bilayer, the amino- and carboxy-terminal regions are located inside the cell, and the segment between the two TMs remains outside of the cell as the extracellular region of ENaC. This extracellular region includes about 70% of the residues of each subunit. Thus, in the membrane-bound form, the bulk of each subunit is located outside of the cell.

The structure of ENaC has not been yet determined. Yet, the structure of a homologous protein ASIC1 has been resolved.<ref name="2007-Jasti">{{cite journal | vauthors = Jasti J, Furukawa H, Gonzales EB, Gouaux E | title = Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH | journal = Nature | volume = 449 | issue = 7160 | pages = 316–23 | date = Sep 2007 | pmid = 17882215 | doi = 10.1038/nature06163 | bibcode = 2007Natur.449..316J }}</ref><ref>{{cite journal | vauthors = Baconguis I, Bohlen CJ, Goehring A, Julius D, Gouaux E | title = X-ray structure of acid-sensing ion channel 1-snake toxin complex reveals open state of a Na(+)-selective channel | journal = Cell | volume = 156 | issue = 4 | pages = 717–29 | date = Feb 2014 | pmid = 24507937 | doi = 10.1016/j.cell.2014.01.011 | pmc=4190031}}</ref> The chicken ASIC1 structure revealed that ASIC1 is assembled as a homotrimer of three identical subunits. The authors of the original study suggested that each ASIC1 subunit resembles a hand holding a ball.<ref name="2007-Jasti" /> Hence distinct domains of ASIC1 have been referred to as palm, knuckle, finger, thumb, and β-ball.<ref name="2007-Jasti" />

Alignment of ENaC subunit sequences with ASIC1 sequence reveals that TM1 and TM2 segments and palm domain are conserved, and the knuckle, finger and thumb domains have insertions in ENaC. Site-directed mutagenesis studies on ENaC subunits provide evidence that many basic features of the ASIC1 structural model apply to ENaC as well. Yet, ENaC is an obligate heterotrimer composed of three subunits as an αβγ or a βγδ trimer.<ref>{{cite journal | vauthors = Hanukoglu I | title = ASIC and ENaC type sodium channels: Conformational states and the structures of the ion selectivity filters | journal = FEBS Journal | volume = 284 | issue= 4 | pages= 525–545 | year= 2017 | pmid= 27580245 | doi= 10.1111/febs.13840 | s2cid = 24402104 | url=https://zenodo.org/record/890906}}</ref>

In the carboxy terminus of three ENaC subunits, (α, β and γ) there is a special conserved consensus sequence PPPXYXXL that is called the PY motif. This sequence is recognized by the so-called [[WW domain]]s in a special E3 ubiquitin-protein ligase named Nedd4-2.<ref name = "2011-Rotin" >{{cite journal | vauthors = Rotin D, Staub O|title = Role of the ubiquitin system in regulating ion transport | journal = Pflügers Archiv: European Journal of Physiology | volume = 461 | issue = 1 |pages = 1–21 | date = Jan 2011 | pmid=20972579 | doi = 10.1007/s00424-010-0893-2|s2cid = 23272309 |url = https://serval.unil.ch/notice/serval:BIB_A1D428672041 }}</ref> Nedd4-2 ligates [[ubiquitin]] to the C-terminus of the ENaC subunit which marks the protein for degradation.<ref name = "2011-Rotin" />

== Associated diseases ==

At present, three major hereditary disorders are known to be associated with mutations in the SCNN1B gene. These are:
1. Multisystem pseudohypoaldosteronism, 2. Liddle syndrome, and 3. Cystic fibrosis-like disease.<ref name="2016-Hanukoglu" />

===Multi-system form of type I pseudohypoaldosteronism (PHA1B)===
The disease most commonly associated with mutations in SCNN1B is the multi-system form of type I pseudohypoaldosteronism (PHA1B) that was first characterized by A. Hanukoglu as an autosomal recessive disease.<ref>{{cite journal | vauthors = Hanukoglu A | title = Type I pseudohypoaldosteronism includes two clinically and genetically distinct entities with either renal or multiple target organ defects | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 73 | issue = 5 | pages = 936–44 | date = Nov 1991 | pmid = 1939532 | doi = 10.1210/jcem-73-5-936 | s2cid = 10717421 | url = https://zenodo.org/record/890914 }}</ref> This is a syndrome of unresponsiveness to aldosterone in patients that have high serum levels of aldosterone but suffer from symptoms of aldosterone deficiency with a high risk of mortality due to severe salt loss. Initially, this disease was thought to be a result of a mutation in the mineralocorticoid receptor (NR3C2) that binds aldosterone. But homozygosity mapping in 11 affected families revealed that the disease is associated with two loci on chromosome 12p13.1-pter and chromosome 16p12.2-13 that include the genes for SCNN1A and SCNN1B and SCNN1G respectively.<ref>{{cite journal | vauthors = Strautnieks SS, Thompson RJ, Hanukoglu A, Dillon MJ, Hanukoglu I, Kuhnle U, Seckl J, Gardiner RM, Chung E | title = Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping | journal = Human Molecular Genetics | volume = 5 | issue = 2 | pages = 293–9 | date = Feb 1996 | pmid = 8824886 | doi=10.1093/hmg/5.2.293| doi-access = }}</ref> Sequencing of the ENaC genes identified mutation in affected patients, and functional expression of the mutated cDNAs further confirmed that identified mutations lead to the loss of activity of ENaC.<ref>{{cite journal | vauthors = Chang SS, Grunder S, Hanukoglu A, Rösler A, Mathew PM, Hanukoglu I, Schild L, Lu Y, Shimkets RA, Nelson-Williams C, Rossier BC, Lifton RP | title = Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1 | journal = Nature Genetics | volume = 12 | issue = 3 | pages = 248–53 | date = Mar 1996 | pmid = 8589714 | doi = 10.1038/ng0396-248 | s2cid = 8185511 }}</ref>

In the majority of the patients with multi-system PHA1B a homozygous mutation or two compound heterozygous mutations have been detected.<ref>{{cite journal | vauthors = Strautnieks SS, Thompson RJ, Gardiner RM, Chung E | title = A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families | journal = Nature Genetics | volume = 13 | issue = 2 | pages = 248–50 | date = Jun 1996 | pmid = 8640238 | doi = 10.1038/ng0696-248 | s2cid = 21124946 }}</ref><ref>{{cite journal | vauthors = Edelheit O, Hanukoglu I, Gizewska M, Kandemir N, Tenenbaum-Rakover Y, Yurdakök M, Zajaczek S, Hanukoglu A | title = Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism | journal = Clinical Endocrinology | volume = 62 | issue = 5 | pages = 547–53 | date = May 2005 | pmid = 15853823 | doi = 10.1111/j.1365-2265.2005.02255.x | s2cid = 2749562 }}</ref><ref>{{cite journal | vauthors = Zennaro MC, Hubert EL, Fernandes-Rosa FL | title = Aldosterone resistance: structural and functional considerations and new perspectives | journal = Molecular and Cellular Endocrinology | volume = 350 | issue = 2 | pages = 206–15 | date = Mar 2012 | pmid = 21664233 | doi = 10.1016/j.mce.2011.04.023 | s2cid = 24896754 }}</ref>

===Liddle syndrome===

Liddle syndrome is generally caused by mutations in the PY motif or truncation of the C-terminus including loss of the PY motif in the β or γ ENaC subunits.<ref>{{cite journal | vauthors = Hansson JH, Nelson-Williams C, Suzuki H, Schild L, Shimkets R, Lu Y, Canessa C, Iwasaki T, Rossier B, Lifton RP | title = Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome | journal = Nat. Genet. | volume = 11 | issue = 1 | pages = 76–82 | year = 1995 | pmid = 7550319 | doi = 10.1038/ng0995-76 | s2cid = 22106822 }}</ref><ref>{{cite journal | vauthors = Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, Gill JR, Ulick S, Milora RV, Findling JW | title = Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel | journal = Cell | volume = 79 | issue = 3 | pages = 407–14 | year = 1994 | pmid = 7954808 | doi = 10.1016/0092-8674(94)90250-X | s2cid = 54282654 }}</ref><ref>{{cite journal | vauthors = Hansson JH, Schild L, Lu Y, Wilson TA, Gautschi I, Shimkets R, Nelson-Williams C, Rossier BC, Lifton RP | title = A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 92 | issue = 25 | pages = 11495–9 | year = 1996 | pmid = 8524790 | pmc = 40428 | doi = 10.1073/pnas.92.25.11495 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Inoue J, Iwaoka T, Tokunaga H, Takamune K, Naomi S, Araki M, Takahama K, Yamaguchi K, Tomita K | title = A family with Liddle's syndrome caused by a new missense mutation in the beta subunit of the epithelial sodium channel | journal = J. Clin. Endocrinol. Metab. | volume = 83 | issue = 6 | pages = 2210–3 | year = 1998 | doi = 10.1210/jcem.83.6.5030 | pmid = 9626162 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Persu A, Barbry P, Bassilana F, Houot AM, Mengual R, Lazdunski M, Corvol P, Jeunemaitre X | title = Genetic analysis of the beta subunit of the epithelial Na+ channel in essential hypertension | journal = Hypertension | volume = 32 | issue = 1 | pages = 129–37 | year = 1998 | pmid = 9674649 | doi = 10.1161/01.hyp.32.1.129 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Uehara Y, Sasaguri M, Kinoshita A, Tsuji E, Kiyose H, Taniguchi H, Noda K, Ideishi M, Inoue J, Tomita K, Arakawa K | title = Genetic analysis of the epithelial sodium channel in Liddle's syndrome | journal = J. Hypertens. | volume = 16 | issue = 8 | pages = 1131–5 | year = 1998 | pmid = 9794716 | doi = 10.1097/00004872-199816080-00008 | s2cid = 31393115 }}</ref> Even though there is a PY motif also in the α subunit, so far Liddle disease has not observed in association with a mutation in the α subunit. Liddle syndrome is inherited as an autosomal dominant disease with a phenotype that includes early onset hypertension, metabolic alkalosis and low levels of plasma renin activity and mineralocorticoid hormone aldosterone. In the absence of a recognizable PY motif, ubiquitin-protein ligase Nedd4-2 cannot bind to the ENaC subunit and hence cannot attach a ubiquitin to it. Consequently, proteolysis of ENaC by proteasome is inhibited and ENaC accumulates in the membrane leading to enhanced activity of ENaC that causes hypertension.<ref>{{cite journal | vauthors = Snyder PM, Price MP, McDonald FJ, Adams CM, Volk KA, Zeiher BG, Stokes JB, Welsh MJ | title = Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel | journal = Cell | volume = 83 | issue = 6 | pages = 969–78 | year = 1996 | pmid = 8521520 | doi = 10.1016/0092-8674(95)90212-0 | s2cid = 970556 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Tamura H, Schild L, Enomoto N, Matsui N, Marumo F, Rossier BC | title = Liddle disease caused by a missense mutation of beta subunit of the epithelial sodium channel gene | journal = J. Clin. Invest. | volume = 97 | issue = 7 | pages = 1780–4 | year = 1996 | pmid = 8601645 | pmc = 507244 | doi = 10.1172/JCI118606 }}</ref><ref>{{cite journal | vauthors = Firsov D, Schild L, Gautschi I, Mérillat AM, Schneeberger E, Rossier BC | title = Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: A quantitative approach | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 93 | issue = 26 | pages = 15370–5 | year = 1997 | pmid = 8986818 | pmc = 26411 | doi = 10.1073/pnas.93.26.15370 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Pirozzi G, McConnell SJ, Uveges AJ, Carter JM, Sparks AB, Kay BK, Fowlkes DM | title = Identification of novel human WW domain-containing proteins by cloning of ligand targets | journal = J. Biol. Chem. | volume = 272 | issue = 23 | pages = 14611–6 | year = 1997 | pmid = 9169421 | doi = 10.1074/jbc.272.23.14611 | doi-access = free | url = https://cdr.lib.unc.edu/downloads/1g05fm824 }}</ref>

== Interactions ==

SCNN1B has been shown to [[Protein-protein interaction|interact]] with [[WWP2]]<ref name=pmid12167593>{{cite journal | vauthors = McDonald FJ, Western AH, McNeil JD, Thomas BC, Olson DR, Snyder PM | title = Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel | journal = Am. J. Physiol. Renal Physiol. | volume = 283 | issue = 3 | pages = F431–6 | date = September 2002 | pmid = 12167593 | doi = 10.1152/ajprenal.00080.2002 }}</ref><ref name=pmid11244092>{{cite journal | vauthors = Harvey KF, Dinudom A, Cook DI, Kumar S | title = The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel | journal = J. Biol. Chem. | volume = 276 | issue = 11 | pages = 8597–601 | date = March 2001 | pmid = 11244092 | doi = 10.1074/jbc.C000906200 | doi-access = free }}</ref> and [[NEDD4]].<ref name=pmid12167593/><ref name=pmid11244092/><ref name=pmid10642508>{{cite journal | vauthors = Farr TJ, Coddington-Lawson SJ, Snyder PM, McDonald FJ | title = Human Nedd4 interacts with the human epithelial Na+ channel: WW3 but not WW1 binds to Na+-channel subunits | journal = Biochem. J. | volume = 345 | issue = 3 | pages = 503–9 | date = February 2000 | pmid = 10642508 | pmc = 1220784 | doi = 10.1042/0264-6021:3450503 }}</ref>

==Notes==
{{Academic-written review
| wikidate = 2015
| journal = [[Gene (journal)|Gene]]
| Q = Q28272095
}}

== References ==
{{Reflist|33em}}

== Further reading ==
{{Refbegin|33em}}
* {{cite journal | vauthors = Alvarez de la Rosa D, Canessa CM, Fyfe GK, Zhang P | title = Structure and regulation of amiloride-sensitive sodium channels | journal = Annu. Rev. Physiol. | volume = 62 | pages = 573–94 | year = 2000 | pmid = 10845103 | doi = 10.1146/annurev.physiol.62.1.573 }}
* {{cite journal | vauthors = Rossier BC, Pradervand S, Schild L, Hummler E | title = Epithelial sodium channel and the control of sodium balance: interaction between genetic and environmental factors | journal = Annu. Rev. Physiol. | volume = 64 | pages = 877–97 | year = 2002 | pmid = 11826291 | doi = 10.1146/annurev.physiol.64.082101.143243 }}
{{Refend}}

== External links ==
* {{MeshName|SCNN1B+protein,+human}}

{{Ion channels|g2}}

{{DEFAULTSORT:Scnn1b}}
[[Category:Sodium channels]]

Furanose

2024-06-04T13:01:17Z

167.201.243.136: Added short description

{{short description|Cyclic carbohydrate}}
[[File:Beta-D-Fructofuranose.svg|thumb|160px|Beta-{{Smallcaps|d}}-fructofuranose]]
A '''furanose''' is a collective term for [[carbohydrates]] that have a chemical structure that includes a five-membered ring system consisting of four carbon atoms and one oxygen atom. The name derives from its similarity to the oxygen heterocycle [[furan]], but the furanose ring does not have [[double bond]]s.<ref name=Furanose>{{cite book
|last1=Reginald |first1=Garrett |last2=Grisham |first2=Charles M. | title=Biochemistry |edition=3rd
| publisher=Cengage Learning
| year=2005
| isbn= 0-534-49033-6 }}</ref>

==Structural properties==
[[File:Ribofuranose-2D-skeletal.png|thumb|right|160px|The chemical structure of [[ribose]] in its furanose form. The wavy bond indicates a mixture of β-ribofuranose and α-ribofuranose.]]

The furanose ring is a cyclic [[hemiacetal]] of an [[aldopentose]] or a cyclic [[hemiketal]] of a [[ketohexose]].

A furanose ring structure consists of four [[carbon]] and one [[oxygen]] atom with the [[anomer]]ic carbon to the right of the oxygen. The highest numbered [[Chirality (chemistry)|chiral]] carbon (typically to the left of the oxygen in a [[Haworth projection]]) determines whether or not the structure has a {{smallcaps|d}}-configuration or L-configuration. In an {{smallcaps|l}}-configuration furanose, the substituent on the highest numbered chiral carbon is pointed downwards out of the plane, and in a D-configuration furanose, the highest numbered chiral carbon is facing upwards.

The furanose ring will have either alpha or beta configuration, depending on which direction the anomeric [[Hydroxyl|hydroxy]] group is pointing. In a {{smallcaps|d}}-configuration furanose, alpha configuration has the hydroxy pointing down, and beta has the hydroxy pointing up. It is the opposite in an {{smallcaps|l}}-configuration furanose. Typically, the anomeric carbon undergoes [[mutarotation]] in solution, and the result is an equilibrium mixture of α and β configurations.

==See also==
* [[Pyranose]]

==References==
{{Reflist}}

{{Carbohydrates}}
{{Authority control}}

[[Category:Carbohydrate chemistry]]
[[Category:Furanoses| ]]

Progerin

2024-05-31T15:42:50Z

167.201.243.136: Clarified that defect is in mature mRNA after splicing

{{short description|Mutant lamin A protein}}
'''Progerin''' (UniProt# P02545-6) is a truncated version of the [[lamin A]] [[protein]] involved in the pathology of [[Hutchinson–Gilford progeria syndrome]]. Progerin is most often generated by a sporadic single point nucleotide polymorphism c.1824 C>T (GGC -> GGT, p.Gly608Gly) in the gene that codes for matured Lamin A.<ref>{{Cite journal |last1=McClintock |first1=Dayle |last2=Gordon |first2=Leslie B. |last3=Djabali |first3=Karima |date=2006-02-14 |title=Hutchinson–Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-Lamin A G608G antibody |journal=Proceedings of the National Academy of Sciences |language=en |volume=103 |issue=7 |pages=2154–2159 |doi=10.1073/pnas.0511133103 |issn=0027-8424 |pmc=1413759 |pmid=16461887|bibcode=2006PNAS..103.2154M |doi-access=free }}</ref> This mutation activates a [[cryptic splice site]] that induces a larger mutation in the processed prelamin A messenger RNA, causing the deletion of a 50 [[amino acid|amino-acid]] group near the [[C-terminus]] of the prelamin A protein.<ref>{{Cite journal |last1=Eriksson |first1=Maria |last2=Brown |first2=W. Ted |last3=Gordon |first3=Leslie B. |last4=Glynn |first4=Michael W. |last5=Singer |first5=Joel |last6=Scott |first6=Laura |last7=Erdos |first7=Michael R. |last8=Robbins |first8=Christiane M. |last9=Moses |first9=Tracy Y. |last10=Berglund |first10=Peter |last11=Dutra |first11=Amalia |date=May 2003 |title=Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome |journal=Nature |language=en |volume=423 |issue=6937 |pages=293–298 |doi=10.1038/nature01629 |pmid=12714972 |pmc=10540076 |bibcode=2003Natur.423..293E |hdl=2027.42/62684 |s2cid=4420150 |issn=0028-0836}}</ref> The endopeptidase [[ZMPSTE24]] cannot cleave between the missing RSY - LLG amino acid sequence (as seen in the figure) during the maturation of Lamin A, due to the deletion of the 50 amino acids which included that sequence. This leaves the intact premature Lamin A bonded to the methylated carboxyl farnesyl group creating the defective protein Progerin, rather than the desired protein matured Lamin A. Approximately 90% of all Hutchinson–Gilford progeria syndrome cases are heterozygous for this deleterious [[single nucleotide polymorphism]] within [[exon]] 11 of the ''LMNA'' gene causing the post-translational modifications to produce progerin.<ref>{{Citation |last1=Gordon |first1=Leslie B. |title=Hutchinson-Gilford Progeria Syndrome |date=1993 |url=http://www.ncbi.nlm.nih.gov/books/NBK1121/ |work=GeneReviews® |editor-last=Adam |editor-first=Margaret P. |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=20301300 |access-date=2022-04-26 |last2=Brown |first2=W. Ted |last3=Collins |first3=Francis S. |editor2-last=Ardinger |editor2-first=Holly H. |editor3-last=Pagon |editor3-first=Roberta A. |editor4-last=Wallace |editor4-first=Stephanie E.}}</ref> [[File:Biogenesis of lamin A in normal cells and the failure to generate mature lamin A in HGPS.jpg|thumb|400px|Normal (left) prelamin A processing and the defective gene Progerin (right) without the 50 AA sequence processing.]]Lamin A constitutes a major structural component of the [[Nuclear lamina|lamina]], a scaffold of proteins found inside the [[nuclear membrane]] of a [[Cell (biology)|cell]]; progerin does not properly integrate into the lamina, which disrupts the scaffold structure and leads to significant disfigurement of the nucleus, characterized by a globular shape.<ref>{{Cite web |title=Anti-cancer Drugs May Hold Promise For Premature Aging Disorder |url=https://www.sciencedaily.com/releases/2005/08/050830065132.htm |access-date=2022-04-26 |website=ScienceDaily |language=en}}</ref> Progerin activates genes that regulate [[stem cell]] [[Cellular differentiation|differentiation]] via the [[Notch signaling pathway]].<ref name=":0">{{Cite journal |last1=Scaffidi |first1=Paola |last2=Misteli |first2=Tom |date=April 2008 |title=Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing |journal=Nature Cell Biology |volume=10 |issue=4 |pages=452–459 |doi=10.1038/ncb1708 |issn=1476-4679 |pmc=2396576 |pmid=18311132}}</ref> Progerin increases the frequency of unrepaired double-strand breaks in DNA following exposure to [[ionizing radiation]].<ref name=":1">{{Cite journal |last1=Noda |first1=Asao |last2=Mishima |first2=Shuji |last3=Hirai |first3=Yuko |last4=Hamasaki |first4=Kanya |last5=Landes |first5=Reid D. |last6=Mitani |first6=Hiroshi |last7=Haga |first7=Kei |last8=Kiyono |first8=Tohru |last9=Nakamura |first9=Nori |last10=Kodama |first10=Yoshiaki |date=December 2015 |title=Progerin, the protein responsible for the Hutchinson-Gilford progeria syndrome, increases the unrepaired DNA damages following exposure to ionizing radiation |journal=Genes and Environment |language=en |volume=37 |issue=1 |pages=13 |doi=10.1186/s41021-015-0018-4 |issn=1880-7062 |pmc=4917958 |pmid=27350809 |doi-access=free }}</ref> Also, overexpression of progerin is correlated with an increase in [[non-homologous end joining]] relative to [[homologous recombination]] among those DNA double-strand breaks that are [[DNA repair|repaired]].<ref>{{Cite journal |last1=Komari |first1=Celina J. |last2=Guttman |first2=Anne O. |last3=Carr |first3=Shelby R. |last4=Trachtenberg |first4=Taylor L. |last5=Orloff |first5=Elise A. |last6=Haas |first6=Ashley V. |last7=Patrick |first7=Andrew R. |last8=Chowdhary |first8=Sona |last9=Waldman |first9=Barbara C. |last10=Waldman |first10=Alan S. |date=December 2020 |title=Alteration of genetic recombination and double-strand break repair in human cells by progerin expression |journal=DNA Repair |language=en |volume=96 |pages=102975 |doi=10.1016/j.dnarep.2020.102975 |pmc=7669652 |pmid=33010688}}</ref> Furthermore, the fraction of homologous recombination events occurring by [[gene conversion]] is increased. These findings suggest that the normal untruncated [[nuclear lamina]] has an important role in the proper [[DNA repair|repair of DNA double-strand breaks]].<ref name=":1" />

== Point mutation ==
c.1824 C>T (GGC -> GGT, p.Gly608Gly) is the single point nucleotide polymorphism that occurs in most patients with progeria. The mutation occurs in the region G608 in exon 11 causing the sporadic mutation resulting in the amino acid [[glycine]] GGC to an alternative version of glycine GGT known as Gly608Gly. This single nucleotide C -> T polymorphism encodes for exon 11 to delete the 50 essential amino acid groups in the maturation of Lamin A.<ref>{{Cite journal |last1=Piekarowicz |first1=Katarzyna |last2=Machowska |first2=Magdalena |last3=Dzianisava |first3=Volha |last4=Rzepecki |first4=Ryszard |date=February 2019 |title=Hutchinson-Gilford Progeria Syndrome—Current Status and Prospects for Gene Therapy Treatment |journal=Cells |language=en |volume=8 |issue=2 |pages=88 |doi=10.3390/cells8020088 |issn=2073-4409 |pmc=6406247 |pmid=30691039|doi-access=free }}</ref> This deletion is then what causes the mutation of premature Lamin A to become the defective protein Progerin.

== Premature aging ==
The defective gene in HGPS Progerin has effects on accelerated aging effects due to the conformational stress Progerin has on the [[cell membrane]]. Matured Lamin A is a protein that maintains the cell's structural stability along with other functions.<ref>{{Cite journal |last1=Dubik |first1=Niina |last2=Mai |first2=Sabine |date=2020-12-09 |title=Lamin A/C: Function in Normal and Tumor Cells |journal=Cancers |language=en |volume=12 |issue=12 |pages=3688 |doi=10.3390/cancers12123688 |issn=2072-6694 |pmc=7764147 |pmid=33316938|doi-access=free }}</ref> The insertion of Progerin protein rather than the normal functioning matured Lamin A results in [[DNA damage]] along the cellular membrane causing stress which activates the protein [[p53]] resulting in premature cellular senescence causing the rapid aging effects you see in HGPS.

== Lonafarnib ==
Researchers are exploring [[lonafarnib]] (a [[farnesyltransferase inhibitor]]) as a potential [[pharmacological therapy]] against the negative effects of Progerin on nuclear morphology in HGPS. lonafarnib, so far is currently the only FDA approved treatment for HGPS.<ref>{{Cite journal |last=Dhillon |first=Sohita |date=February 2021 |title=Lonafarnib: First Approval |journal=Drugs |language=en |volume=81 |issue=2 |pages=283–289 |doi=10.1007/s40265-020-01464-z |issn=0012-6667 |pmc=7985116 |pmid=33590450}}</ref>

=== Other information ===
Recently, [[rapamycin]] has been shown to prevent Progerin aggregates in cells and hence delay premature aging.

Progerin, which has been linked to normal [[Ageing|aging]], is produced in healthy individuals via "sporadic use of the cryptic splice site".<ref name=":0" /><ref>{{Cite journal |last1=Liu |first1=Baohua |last2=Zhou |first2=Zhongjun |date=June 2008 |title=Lamin A/C, laminopathies and premature ageing |url=https://pubmed.ncbi.nlm.nih.gov/18366013 |journal=Histology and Histopathology |volume=23 |issue=6 |pages=747–763 |doi=10.14670/HH-23.747 |issn=1699-5848 |pmid=18366013}}</ref>

==References==
<references />

[[Category:Aging-related proteins]]
[[Category:Human proteins]]

DCLK1

2024-05-30T22:48:19Z

167.201.243.136: Added wikilink

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{cs1 config|name-list-style=vanc}}
{{Infobox_gene}}
'''Doublecortin-like kinase protein 1''' ('''DCLK1''')<ref name="pmid9747029">{{cite journal | vauthors = Omori Y, Suzuki M, Ozaki K, Harada Y, Nakamura Y, Takahashi E, Fujiwara T | title = Expression and chromosomal localization of KIAA0369, a putative kinase structurally related to Doublecortin | journal = J Hum Genet | volume = 43 | issue = 3 | pages = 169–77 |date=Oct 1998 | pmid = 9747029 | doi = 10.1007/s100380050063 | doi-access = free }}</ref><ref name="pmid10036192">{{cite journal | vauthors = Sossey-Alaoui K, Srivastava AK | title = DCAMKL1, a brain-specific transmembrane protein on 13q12.3 that is similar to doublecortin (DCX) | journal = Genomics | volume = 56 | issue = 1 | pages = 121–6 |date=May 1999 | pmid = 10036192 | doi = 10.1006/geno.1998.5718 }}</ref><ref name=ding2023>{{cite journal|vauthors=Ding L, Weygant N, Ding C, Lai Y, Li H|title=DCLK1 and tuft cells: Immune-related functions and implications for cancer immunotherapy|journal=Critical Reviews in Oncology and Hematology|volume=191|id=Art. No. 104118|year=2023|doi=10.1016/j.critrevonc.2023.104118|pmid=37660932}}</ref><ref name="entrez">{{cite web | title = Entrez Gene: DCAMKL1 doublecortin and CaM kinase-like 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9201|access-date=30 May 2024|date=7 April 2024|website=Gene|publisher=National Library of Medicine}}</ref> is an [[enzyme]] that in humans is encoded by the ''DCLK1'' [[gene]].<ref name="pmid9747029"/><ref name="pmid10036192"/><ref name="entrez"/> Its C-terminal domain in rats is expressed independently from an alternative transcript, ''cpg16'', and can function alone as a [[serine/threonine protein kinase]] that is [[cyclic AMP]] dependent.<ref>{{cite journal|vauthors=Silverman MA, Benard O, Jaaro H, Rattner A, Citri Y, Seger R|title=CPG16, a novel protein serine/threonine kinase downstream of cAMP-dependent protein kinase|journal=Journal of Biological Chemistry|year=1999|volume=274|issue=5|pages=2631-2636|doi-access=free|pmid=9915791|doi=10.1074/jbc.274.5.2631}}</ref><ref>{{cite journal | vauthors=Lin PT, Gleeson JG, Corbo JC |title=DCAMKL1 encodes a protein kinase with homology to doublecortin that regulates microtubule polymerization. |journal=J. Neurosci. |volume=20 |issue= 24 |pages= 9152–61 |year= 2001 |pmid= 11124993 |doi= 10.1523/JNEUROSCI.20-24-09152.2000|pmc=6773030 |display-authors=etal|doi-access=free }}</ref>

DCLK1 expression is a marker for [[tuft cells]], a type of chemosensory cell of the intestinal epithelium.<ref name=ding2023/><ref>{{cite journal|vauthors=Gerbe F, Legraverend C, Jay P|title=The intestinal epithelium tuft cells: specification and function|journal=Cellular and Molecular Life Sciences|volume=69|pages=2907-2917|year=2012|issue=17|pmid=22527717|pmc=3417095|doi=10.1007/s00018-012-0984-7|doi-access=free}}</ref>

==References==
{{reflist}}

==Further reading==
{{refbegin | 2}}
*{{cite journal | vauthors=Nagase T, Ishikawa K, Nakajima D |title=Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. |journal=DNA Res. |volume=4 |issue= 2 |pages= 141–50 |year= 1997 |pmid= 9205841 |doi=10.1093/dnares/4.2.141 |display-authors=etal|doi-access=free }}
*{{cite journal | vauthors=Matsumoto N, Pilz DT, Ledbetter DH |title=Genomic structure, chromosomal mapping, and expression pattern of human DCAMKL1 (KIAA0369), a homologue of DCX (XLIS). |journal=Genomics |volume=56 |issue= 2 |pages= 179–83 |year= 1999 |pmid= 10051403 |doi= 10.1006/geno.1998.5673 }}
*{{cite journal | vauthors=Burgess HA, Reiner O |title=Alternative splice variants of doublecortin-like kinase are differentially expressed and have different kinase activities. |journal=J. Biol. Chem. |volume=277 |issue= 20 |pages= 17696–705 |year= 2002 |pmid= 11884394 |doi= 10.1074/jbc.M111981200 |doi-access= free }}
*{{cite journal | vauthors=Kim MH, Derewenda U, Devedjiev Y |title=Purification and crystallization of the N-terminal domain from the human doublecortin-like kinase. |journal=Acta Crystallogr. D |volume=59 |issue= Pt 3 |pages= 502–5 |year= 2003 |pmid= 12595708 |doi=10.1107/S0907444903000027 |bibcode=2003AcCrD..59..502K |display-authors=etal}}
*{{cite journal | vauthors=Kim MH, Cierpicki T, Derewenda U |title=The DCX-domain tandems of doublecortin and doublecortin-like kinase. |journal=Nat. Struct. Biol. |volume=10 |issue= 5 |pages= 324–33 |year= 2003 |pmid= 12692530 |doi= 10.1038/nsb918 |s2cid=10173864 |display-authors=etal}}
*{{cite journal | vauthors=Seet LF, Liu N, Hanson BJ, Hong W |title=Endofin recruits TOM1 to endosomes. |journal=J. Biol. Chem. |volume=279 |issue= 6 |pages= 4670–9 |year= 2004 |pmid= 14613930 |doi= 10.1074/jbc.M311228200 |doi-access= free }}
*{{cite journal | vauthors=Ballif BA, Villén J, Beausoleil SA |title=Phosphoproteomic analysis of the developing mouse brain. |journal=Mol. Cell. Proteomics |volume=3 |issue= 11 |pages= 1093–101 |year= 2005 |pmid= 15345747 |doi= 10.1074/mcp.M400085-MCP200 |display-authors=etal|doi-access=free }}
{{refend}}

== External links ==
* {{PDBe-KB2|O15075|Serine/threonine-protein kinase DCLK1}}

{{PDB Gallery|geneid=9201}}
{{Serine/threonine-specific protein kinases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

[[Category:EC 2.7.11]]

{{gene-13-stub}}

Nuclear cap-binding protein complex

2024-05-30T15:46:48Z

167.201.243.136: Section headers to sentence case per MOS:HEADINGS

{{cs1 config|name-list-style=vanc}}
{{short description|RNA-binding protein}}
{{infobox protein
| Name = nuclear cap-binding protein complex
| caption = Crystal structure of the human nuclear cap-binding complex.<ref name="pmid11545740">{{PDB|1H6K}}; {{cite journal | vauthors = Mazza C, Ohno M, Segref A, Mattaj IW, Cusack S | title = Crystal structure of the human nuclear cap binding complex | journal = Molecular Cell | volume = 8 | issue = 2 | pages = 383–396 | date = August 2001 | pmid = 11545740 | doi = 10.1016/S1097-2765(01)00299-4 | doi-access = free }}</ref>
| image = 1H6K.pdb.jpg
| width =
| HGNCid = 7658
| Symbol = NCBP1
| AltSymbols = NCBP
| EntrezGene = 4686
| OMIM =
| RefSeq = NM_002486
| UniProt =
| PDB =
| ECnumber =
| Chromosome = 9
| Arm = q
| Band = 34.1
| LocusSupplementaryData =
}}
{{infobox protein
|Name=Nuclear cap binding protein subunit 2, 20kDa
|caption=
|image=
|width=
|HGNCid=7659
|Symbol=NCBP2
|AltSymbols=
|EntrezGene=22916
|OMIM=605133
|RefSeq=NM_007362
|UniProt=P52298
|PDB=
|ECnumber=
|Chromosome=3
|Arm=q
|Band=29
|LocusSupplementaryData=
}}

'''Nuclear cap-binding protein complex''' is a [[RNA-binding protein]] which binds to the [[5' cap]] of [[pre-mRNA]]. The cap and nuclear cap-binding protein have many functions in mRNA [[biogenesis]] including splicing, 3'-end formation by stabilizing the interaction of the 3'-end processing machinery, nuclear export and protection of the transcripts from nuclease degradation.<ref name="pmid19864257">{{cite journal | vauthors = Raczynska KD, Simpson CG, Ciesiolka A, Szewc L, Lewandowska D, McNicol J, Szweykowska-Kulinska Z, Brown JW, Jarmolowski A | display-authors = 6 | title = Involvement of the nuclear cap-binding protein complex in alternative splicing in Arabidopsis thaliana | journal = Nucleic Acids Research | volume = 38 | issue = 1 | pages = 265–278 | date = January 2010 | pmid = 19864257 | pmc = 2800227 | doi = 10.1093/nar/gkp869 }}</ref> During mRNA export, the nuclear cap-binding protein complex recruits ribosomes to begin the pioneer round of translation.<ref name="Choe-2012">{{cite journal | vauthors = Choe J, Oh N, Park S, Lee YK, Song OK, Locker N, Chi SG, Kim YK | display-authors = 6 | title = Translation initiation on mRNAs bound by nuclear cap-binding protein complex CBP80/20 requires interaction between CBP80/20-dependent translation initiation factor and eukaryotic translation initiation factor 3g | journal = The Journal of Biological Chemistry | volume = 287 | issue = 22 | pages = 18500–18509 | date = May 2012 | pmid = 22493286 | pmc = 3365721 | doi = 10.1074/jbc.M111.327528 | doi-access = free }}</ref> When RNA is exported to the [[cytoplasm]] the nuclear cap-binding protein complex is replaced by cytoplasmic cap binding complex. The nuclear cap-binding complex is a functional [[heterodimer]] and composed of Cbc1/Cbc2 in yeast and CBP20/CBP80 in multicellular eukaryotes. Human nuclear cap-binding protein complex shows the large subunit, CBP80 consists of 757 [[amino acid]] residues. Its [[Biomolecular structure#Secondary structure|secondary]] structure contains approximately sixty percent of [[alpha helix|helical]] and one percent of [[beta sheet]] in the strand. The small subunit, CBP20 has 98 [[amino acid residue]]s. Its secondary structure contains approximately twenty percent of helical and twenty-four percent of beta sheet in the strand.<ref name="pmid11545740"/> Human nuclear cap-binding protein complex plays important role in the maturation of pre-[[messenger RNA|mRNA]] and in uracil-rich [[small nuclear RNA]].<ref name="pmid12374755">{{cite journal | vauthors = Mazza C, Segref A, Mattaj IW, Cusack S | title = Large-scale induced fit recognition of an m(7)GpppG cap analogue by the human nuclear cap-binding complex | journal = The EMBO Journal | volume = 21 | issue = 20 | pages = 5548–5557 | date = October 2002 | pmid = 12374755 | pmc = 129070 | doi = 10.1093/emboj/cdf538 }}</ref>

[[File:Cap-binding complex 1H2T.png|thumb|283x283px|Nuclear cap-binding protein complex]]

== Structure ==
In eukaryotes, the nuclear cap-binding protein complex is a heterodimer that is composed of two subunits, CBP80 and CBP20. The CBP20 subunit binds to the cap while CBP80 ensures high-affinity cap binding. The CBP80 is a superhelical structure and it is made up of three domains that are connected by two linkers. Domain 1 of CBP80 plays an important role in cap-dependent translation of mRNA. CBP80 ensures high-affinity cap binding by stabilizing the N-terminal loop of CBP20 which locks the cap-binding protein complex into a high-affinity cap-binding state. The CBP20 is composed of the C-terminus, the RNP domain, and the N-terminus. The CBP20 goes through a conformational change when it is bound to the pre-mRNA, it transitions from an open state to a closed, folded state. The conformational change results from a hinge-like motion of the N terminus from the alpha helixes in the α2–α3 loop towards the β-sheets. There is little change in the RNP region of CBP20 in the bound and un-bound states, which indicates this region may act as the initial binding site for the cap structure.<ref name="Calero-2002">{{cite journal | vauthors = Calero G, Wilson KF, Ly T, Rios-Steiner JL, Clardy JC, Cerione RA | title = Structural basis of m7GpppG binding to the nuclear cap-binding protein complex | journal = Nature Structural Biology | volume = 9 | issue = 12 | pages = 912–917 | date = December 2002 | pmid = 12434151 | doi = 10.1038/nsb874 | s2cid = 37901456 }}</ref>

== Role in translation ==
In mammals, the nuclear cap-binding complex can drive and is necessary to initiate the translation of mRNA through cap-binding complex-dependent translation. The cap-binding complex-dependent translation has an important role in protein synthesis and mRNA surveillance. The translation of nuclear cap-binding complex-bound mRNA serves to control the quality of gene expression, while the translation of eIF4E-bound mRNAs serves to produce the majority of proteins.<ref name="Isken-2008">{{cite journal | vauthors = Isken O, Maquat LE | title = The multiple lives of NMD factors: balancing roles in gene and genome regulation | journal = Nature Reviews. Genetics | volume = 9 | issue = 9 | pages = 699–712 | date = September 2008 | pmid = 18679436 | pmc = 3711694 | doi = 10.1038/nrg2402 }}</ref> However, both of these mRNAs use many of the same translation initiation factors; such as PABPC1, eIF4G, eIF3, eIF4B, eIF4A and eIF2.<ref name="Isken-2008" /><ref name="Maquat-2010">{{cite journal | vauthors = Maquat LE, Tarn WY, Isken O | title = The pioneer round of translation: features and functions | journal = Cell | volume = 142 | issue = 3 | pages = 368–374 | date = August 2010 | pmid = 20691898 | pmc = 2950652 | doi = 10.1016/j.cell.2010.07.022 }}</ref> Translation is started when the 40S ribosomal subunit binds to the nuclear cap-binding protein complex and finds the start codon through a scanning complex in the 5' to 3' direction. The first round of translation is primarily mediated by the nuclear cap-binding protein complex, since freshly synthesized mRNA have a 5'-end cap that is bound to the nuclear cap-binding protein complex.<ref name="Ryu-2017">{{cite journal | vauthors = Ryu I, Kim YK | title = Translation initiation mediated by nuclear cap-binding protein complex | journal = BMB Reports | volume = 50 | issue = 4 | pages = 186–193 | date = April 2017 | pmid = 28088948 | pmc = 5437962 | doi = 10.5483/bmbrep.2017.50.4.007 }}</ref> The cap-binding site of the nuclear cap-binding protein complex needs to be regulated so the pre-mRNA can lose this complex and become mature RNA.<ref name="Calero-2002" /> In some instances, the nuclear cap-binding complex is replaced by eIF4E in a translation-independent manner in order to continue translation of the mRNA. To finish creating mature mRNA the nuclear cap-binding protein complex is bound to a 5’-m7GpppN cap structure, the cap structure then binds to the eukaryotic translation initiation factor 4E (eIF4E) which directs steady-state rounds of mRNA translation. This process of translation changes from cap-binding complex dependent translation to eIF4E-dependent translation.<ref name="Ryu-2017" />

== Role in quality assurance ==

=== Quality assurance during pioneer round ===
The nuclear cap-binding protein complex supports the pioneer round of mRNA translation, this pioneer round is important for mRNA quality control. The pioneer round consists of the loading of one or more ribosomes, depending on the efficacy of translation initiation and the length of the open translational reading frame in order to remove premature stop codons.<ref name="Isken-2008" /><ref>{{cite journal | vauthors = Isken O, Kim YK, Hosoda N, Mayeur GL, Hershey JW, Maquat LE | title = Upf1 phosphorylation triggers translational repression during nonsense-mediated mRNA decay | journal = Cell | volume = 133 | issue = 2 | pages = 314–327 | date = April 2008 | pmid = 18423202 | pmc = 4193665 | doi = 10.1016/j.cell.2008.02.030 }}</ref> It is thought that the CBP80 subunit could be an effector of the pioneer stage since the binding of the nuclear cap-binding protein complex to the cap site is stimulated by growth factors during the G1/S phase.<ref name="Maquat-2010" />

=== Quality assurance through nonsense-mediated decay ===
The nuclear cap-binding complex has a larger role in mRNA quality control than it does in actual protein synthesis.<ref name="Ryu-2017" /> One of the ways that it does this quality control is through nonsense-mediated decay. Nonsense-mediated decay is when faulty mRNA's that have stop codons too early are recognized by the SURF complex and down-regulated.<ref name="Choe-2012" /><ref name="Maquat-2010" /> Nonsense-mediated decay is thought to be triggered when the first ribosome that translated a new nuclear cap-binding protein complex-bound mRNA has a stop codon that is found more than 50-55 nucleotides upstream of an exon-junction complex-bearing exon-exon junction.<ref name="Maquat-2010" /> The nuclear cap-binding complex is crucial to nonsense-mediated decay because it makes up the mRNP that harbors the exon-junction complex and because CBP80 directly interacts with the nonsense-mediated decay factor, up-frameshift 1 (UPF1) which amplifies the efficiency of the whole process. The nuclear cap-binding complex is largely important in this process as it has been found that nonsense-mediated decay is only found in nuclear cap-binding complex-bound mRNA.<ref name="Isken-2008" />

== Stress conditions ==
Nuclear cap-binding complex-dependent translation was found to be relatively unaffected by certain environmental stressors such as in hypoxic, heat shock, or serum-starved conditions, while eIF4E-dependent translation was found to be greatly affected.<ref name="Maquat-2010" /><ref name="Ryu-2017" /> In heat shock and serum-starved conditions nuclear cap-binding complex-dependent translation is greatly favored over eIF4E-dependent translation.<ref>{{cite journal | vauthors = Oh N, Kim KM, Cho H, Choe J, Kim YK | title = Pioneer round of translation occurs during serum starvation | journal = Biochemical and Biophysical Research Communications | volume = 362 | issue = 1 | pages = 145–151 | date = October 2007 | pmid = 17693387 | doi = 10.1016/j.bbrc.2007.07.169 }}</ref><ref>{{cite journal | vauthors = Marín-Vinader L, van Genesen ST, Lubsen NH | title = mRNA made during heat shock enters the first round of translation | journal = Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression | volume = 1759 | issue = 11–12 | pages = 535–542 | date = November 2006 | pmid = 17118471 | doi = 10.1016/j.bbaexp.2006.10.003 }}</ref> This could mean that nuclear cap-binding complex-dependent translation has the potential to support translation in high stress environments.<ref name="Ryu-2017" />

== References ==
{{Reflist}}

== External links ==
* {{MeshName|nuclear+cap-binding+protein+complex}}

[[Category:RNA-binding proteins]]

S1PR3

2024-05-28T14:58:12Z

167.201.243.136: Italicized gene abbreviation

{{Short description|Protein and coding gene in humans}}
{{Infobox_gene}}
'''Sphingosine-1-phosphate receptor 3''' also known as '''''S1PR3''''' is a human [[gene]] which encodes a [[G protein-coupled receptor]] which binds the lipid signaling molecule [[sphingosine 1-phosphate]] (S1P). Hence this receptor is also known as '''S1P3'''.<ref name="entrez">{{cite web | title = Entrez Gene: S1PR3 sphingosine-1-phosphate receptor 3 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1903}}</ref>

== Function ==

This gene encodes a member of the EDG family of receptors, which are G protein-coupled receptors. This protein has been identified as a functional receptor for sphingosine 1-phosphate and likely contributes to the regulation of angiogenesis and vascular endothelial cell function.<ref name="entrez"/>

== Evolution ==

=== [[Sequence homology|Paralogues]] to S1PR3 [[Gene]]<ref>{{Cite web |title=GeneCards®: The Human Gene Database |url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=S1PR3#paralogs}}</ref> ===

* [[S1PR1]]
* [[S1PR5]]
* [[S1PR2]]
* [[S1PR4]]
* [[LPAR1]]
* [[LPAR3]]
* [[LPAR2]]
* [[Cannabinoid receptor 1|CNR1]]
* [[Melanocortin 5 receptor|MC5R]]
* [[GPR6]]
* [[GPR12]]
* [[Melanocortin 4 receptor|MC4R]]
* [[Cannabinoid receptor 2|CNR2]]
* [[GPR3]]
* [[Melanocortin 3 receptor|MC3R]]
* [[ACTH receptor|MC2R]]
* [[GPR119]]
* [[Melanocortin 1 receptor|MC1R]]

==See also==
* [[Lysophospholipid receptor]]

==References==
{{reflist}}

==Further reading==
{{refbegin | 2}}
*{{cite journal |vauthors=Hla T, Lee MJ, Ancellin N, etal |title=Sphingosine-1-phosphate signaling via the EDG-1 family of G-protein-coupled receptors. |journal=Ann. N. Y. Acad. Sci. |volume=905 |pages= 16–24 |year= 2000 |issue=1 |pmid= 10818438 |doi= 10.1111/j.1749-6632.2000.tb06534.x |bibcode=2000NYASA.905...16H |s2cid=19435541 }}
*{{cite journal | author=Spiegel S |title=Sphingosine 1-phosphate: a ligand for the EDG-1 family of G-protein-coupled receptors. |journal=Ann. N. Y. Acad. Sci. |volume=905 |pages= 54–60 |year= 2000 |issue=1 |pmid= 10818441 |doi= 10.1111/j.1749-6632.2000.tb06537.x|bibcode=2000NYASA.905...54S |s2cid=9257870 }}
*{{cite journal | vauthors=Watsky MA, Griffith M, Wang DA, Tigyi GJ |title=Phospholipid growth factors and corneal wound healing. |journal=Ann. N. Y. Acad. Sci. |volume=905 |pages= 142–58 |year= 2000 |issue=1 |pmid= 10818450 |doi= 10.1111/j.1749-6632.2000.tb06546.x |bibcode=2000NYASA.905..142W |s2cid=9789496 }}
*{{cite journal | author=Takuwa Y |title=[Regulation of Rho family G proteins and cell motility by the Edg family of sphingosin 1-phosphate receptors] |journal=Tanpakushitsu Kakusan Koso |volume=47 |issue= 4 Suppl |pages= 496–502 |year= 2002 |pmid= 11915348 }}
*{{cite journal |vauthors=Van Koppen CJ, Meyer Zu Heringdorf D, Zhang C, etal |title=A distinct G(i) protein-coupled receptor for sphingosylphosphorylcholine in human leukemia HL-60 cells and human neutrophils. |journal=Mol. Pharmacol. |volume=49 |issue= 6 |pages= 956–61 |year= 1996 |pmid= 8649355 }}
*{{cite journal | vauthors=Yamaguchi F, Tokuda M, Hatase O, Brenner S |title=Molecular cloning of the novel human G protein-coupled receptor (GPCR) gene mapped on chromosome 9. |journal=Biochem. Biophys. Res. Commun. |volume=227 |issue= 2 |pages= 608–14 |year= 1996 |pmid= 8878560 |doi= 10.1006/bbrc.1996.1553 }}
*{{cite journal |vauthors=An S, Bleu T, Huang W, etal |title=Identification of cDNAs encoding two G protein-coupled receptors for lysosphingolipids. |journal=FEBS Lett. |volume=417 |issue= 3 |pages= 279–82 |year= 1998 |pmid= 9409733 |doi=10.1016/S0014-5793(97)01301-X |s2cid=26300053 |doi-access=free }}
*{{cite journal |vauthors=Van Brocklyn JR, Tu Z, Edsall LC, etal |title=Sphingosine 1-phosphate-induced cell rounding and neurite retraction are mediated by the G protein-coupled receptor H218. |journal=J. Biol. Chem. |volume=274 |issue= 8 |pages= 4626–32 |year= 1999 |pmid= 9988698 |doi=10.1074/jbc.274.8.4626 |doi-access=free }}
*{{cite journal |vauthors=Zhang Q, Peyruchaud O, French KJ, etal |title=Sphingosine 1-phosphate stimulates fibronectin matrix assembly through a Rho-dependent signal pathway. |journal=Blood |volume=93 |issue= 9 |pages= 2984–90 |year= 1999 |pmid= 10216094 |doi= 10.1182/blood.V93.9.2984}}
*{{cite journal | vauthors=Ancellin N, Hla T |title=Differential pharmacological properties and signal transduction of the sphingosine 1-phosphate receptors EDG-1, EDG-3, and EDG-5. |journal=J. Biol. Chem. |volume=274 |issue= 27 |pages= 18997–9002 |year= 1999 |pmid= 10383399 |doi=10.1074/jbc.274.27.18997 |doi-access=free }}
*{{cite journal |vauthors=Windh RT, Lee MJ, Hla T, etal |title=Differential coupling of the sphingosine 1-phosphate receptors Edg-1, Edg-3, and H218/Edg-5 to the G(i), G(q), and G(12) families of heterotrimeric G proteins. |journal=J. Biol. Chem. |volume=274 |issue= 39 |pages= 27351–8 |year= 1999 |pmid= 10488065 |doi=10.1074/jbc.274.39.27351 |doi-access=free }}
*{{cite journal |vauthors=Goetzl EJ, Dolezalova H, Kong Y, etal |title=Distinctive expression and functions of the type 4 endothelial differentiation gene-encoded G protein-coupled receptor for lysophosphatidic acid in ovarian cancer. |journal=Cancer Res. |volume=59 |issue= 20 |pages= 5370–5 |year= 1999 |pmid= 10537322 }}
*{{cite journal |vauthors=Lee MJ, Thangada S, Claffey KP, etal |title=Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. |journal=Cell |volume=99 |issue= 3 |pages= 301–12 |year= 1999 |pmid= 10555146 |doi=10.1016/S0092-8674(00)81661-X |s2cid=1126846 |doi-access=free }}
*{{cite journal | vauthors=An S, Zheng Y, Bleu T |title=Sphingosine 1-phosphate-induced cell proliferation, survival, and related signaling events mediated by G protein-coupled receptors Edg3 and Edg5. |journal=J. Biol. Chem. |volume=275 |issue= 1 |pages= 288–96 |year= 2000 |pmid= 10617617 |doi=10.1074/jbc.275.1.288 |doi-access=free }}
*{{cite journal |vauthors=Orlati S, Porcelli AM, Hrelia S, etal |title=Sphingosine-1-phosphate activates phospholipase D in human airway epithelial cells via a G protein-coupled receptor. |journal=Arch. Biochem. Biophys. |volume=375 |issue= 1 |pages= 69–77 |year= 2000 |pmid= 10683250 |doi= 10.1006/abbi.1999.1589 }}
*{{cite journal | vauthors=Lee H, Goetzl EJ, An S |title=Lysophosphatidic acid and sphingosine 1-phosphate stimulate endothelial cell wound healing. |journal=Am. J. Physiol., Cell Physiol. |volume=278 |issue= 3 |pages= C612–8 |year= 2000 |pmid= 10712250 |doi= 10.1152/ajpcell.2000.278.3.C612|s2cid=10976499 }}
*{{cite journal |vauthors=Kimura T, Watanabe T, Sato K, etal |title=Sphingosine 1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3. |journal=Biochem. J. |volume=348 |issue= 1|pages= 71–6 |year= 2000 |pmid= 10794715 |doi=10.1042/0264-6021:3480071 |pmc=1221037}}
{{refend}}

==External links==
*{{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2995 | title = Lysophospholipid Receptors: S1P3 | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2008-12-05 | archive-date = 2016-03-03 | archive-url = https://web.archive.org/web/20160303214242/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2995 | url-status = dead }}
* {{MeshName|Lysophospholipid+receptors}}

{{G protein-coupled receptors}}
{{NLM content}}

[[Category:G protein-coupled receptors]]
{{transmembranereceptor-stub}}

Mitochondrial trifunctional protein

2024-05-17T15:55:00Z

167.201.243.136: Added citation needed flag

{{short description|Inner mitochondrial membrane protein}}
{{distinguish|microsomal triglyceride transfer protein}}
[[Image:LCHAD deficiency.svg|right|thumb|400px|Schematic demonstrating [[mitochondria]]l [[fatty acid]] [[beta-oxidation]] and effects of [[long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency|long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, LCHAD deficiency]]]]
'''Mitochondrial trifunctional protein (MTP)''' is a [[protein]] attached to the [[inner mitochondrial membrane]] which [[Catalysis|catalyzes]] three out of the four steps in [[beta oxidation]]. MTP is a hetero-octamer composed of four alpha and four beta subunits:

* [[HADHA]]
* [[HADHB]]

The three functions are [[2-enoyl coenzyme A (CoA) hydratase]], [[long-chain 3-hydroxy acyl-coenzyme A dehydrogenase]] and [[long-chain 3-ketoacyl CoA thiolase]].<ref name="urlLong-Chain Acyl CoA Dehydrogenase Deficiency: eMedicine Pediatrics: Genetics and Metabolic Disease">{{cite web |url=http://emedicine.medscape.com/article/945857-overview |title=Long-Chain Acyl CoA Dehydrogenase Deficiency: eMedicine Pediatrics: Genetics and Metabolic Disease |format= |accessdate=2009-07-11}}</ref>

==Association with the electron transport chain==
Fatty acid beta-oxidation (FAO) and [[oxidative phosphorylation]] (OXPHOS) are two major metabolic pathways in the [[mitochondria]]. Reducing equivalents from FAO enter OXPHOS at the level of [[complex I|complexes I]] and [[complex III|III]]. In 2010, Wang ''et al.'' discovered a functional and physical association between MTP and ETC [[respirasomes]]. Not only does MTP appear to be bound to Complex I, but it also appears to [[substrate channelling|channel substrates]] between the two enzymes.<ref name="WangMohsen2010">{{cite journal|last1=Wang|first1=Y.|last2=Mohsen|first2=A.-W.|last3=Mihalik|first3=S. J.|last4=Goetzman|first4=E. S.|last5=Vockley|first5=J.|title=Evidence for Physical Association of Mitochondrial Fatty Acid Oxidation and Oxidative Phosphorylation Complexes|journal=Journal of Biological Chemistry|volume=285|issue=39|year=2010|pages=29834–29841|issn=0021-9258|doi=10.1074/jbc.M110.139493|pmid=20663895|pmc=2943265|doi-access=free}}</ref> This is especially interesting, because up until then it was unknown exactly how MTP was associated with the inner mitochondrial membrane, and this discovery may provide the explanation.

==Hormonal influences==
Recent research has revealed that MTP can be affected by various [[hormones]], via [[hormone receptors]] located in the mitochondria. Chochron ''et al.'' (2012) demonstrated that [[thyroid hormone]] stimulates mitochondrial [[metabolism]] in a pathway mediated by MTP.<ref name="ChocronSayre2012">{{cite journal|last1=Chocron|first1=E. S.|last2=Sayre|first2=N. L.|last3=Holstein|first3=D.|last4=Saelim|first4=N.|last5=Ibdah|first5=J. A.|last6=Dong|first6=L. Q.|last7=Zhu|first7=X.|last8=Cheng|first8=S.-Y.|last9=Lechleiter|first9=J. D.|title=The Trifunctional Protein Mediates Thyroid Hormone Receptor-Dependent Stimulation of Mitochondria Metabolism|journal=Molecular Endocrinology|volume=26|issue=7|year=2012|pages=1117–1128|issn=0888-8809|doi=10.1210/me.2011-1348|pmid=22570332|pmc=3385793}}</ref> Zhou ''et al.'' (2012) used [[Two-dimensional gel electrophoresis|2D gel electrophoresis]] and [[mass spectrometry]] to identify MTP as one of the proteins that interacts with [[Estrogen receptor alpha|ER alpha]], a receptor triggered by [[estrogen]].<ref name="ZhouZhou2012">{{cite journal|last1=Zhou|first1=Z.|last2=Zhou|first2=J.|last3=Du|first3=Y.|title=Estrogen Receptor Alpha Interacts with Mitochondrial Protein HADHB and Affects Beta-Oxidation Activity|journal=Molecular & Cellular Proteomics|volume=11|issue=7|year=2012|pages=M111.011056|issn=1535-9476|doi=10.1074/mcp.M111.011056|doi-access=free |pmid=22375075|pmc=3394935}}</ref>

==Cardiolipin remodeling==
In 2009, Taylor ''et al.'' identified a human mitochondrial protein, [[monolysocardiolipin acyltransferase|monolysocardiolipin acyltransferase (MLCL AT-1)]], that is identical in [[amino acid sequence]] to the 59-kDa [[C-terminal]] end of MTP, linking MTP to the remodeling of [[cardiolipin]] from [[monolysocardiolipin]].<ref name="TaylorHatch2009">{{cite journal|last1=Taylor|first1=W. A.|last2=Hatch|first2=G. M.|title=Identification of the Human Mitochondrial Linoleoyl-coenzyme A Monolysocardiolipin Acyltransferase (MLCL AT-1)|journal=Journal of Biological Chemistry|volume=284|issue=44|year=2009|pages=30360–30371|issn=0021-9258|doi=10.1074/jbc.M109.048322|pmid=19737925|pmc=2781591|doi-access=free}}</ref> Although MLCL AT-1 and MTP are different proteins, in 2012 the same lab discovered that MTP did indeed have cardiolipin remodeling capabilities.<ref name="BehTaylor2012">{{cite journal|last1=Beh|first1=Christopher|last2=Taylor|first2=William A.|last3=Mejia|first3=Edgard M.|last4=Mitchell|first4=Ryan W.|last5=Choy|first5=Patrick C.|last6=Sparagna|first6=Genevieve C.|last7=Hatch|first7=Grant M.|title=Human Trifunctional Protein Alpha Links Cardiolipin Remodeling to Beta-Oxidation|journal=PLOS ONE|volume=7|issue=11|year=2012|pages=e48628|issn=1932-6203|doi=10.1371/journal.pone.0048628|pmid=23152787|pmc=3494688|bibcode=2012PLoSO...748628T|doi-access=free}}</ref> This suggests a possible link between mitochondrial membrane cardiolipin content and [[beta oxidation]].

==Clinical significance==
Disorders associated with MTP are:{{citation needed|date=May 2024}}

* [[Mitochondrial trifunctional protein deficiency]]
* [[Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency|LCHAD deficiency]]
* [[Acute fatty liver of pregnancy]]

==References==
{{reflist|2}}

==External links==
* {{MeshName|mitochondrial+trifunctional+protein+TP}}

{{Multienzyme complexes}}
{{Lipid metabolism enzymes}}
{{Mitochondrial enzymes}}

[[Category:Proteins]]

N-acetyltransferase

2024-05-17T14:10:23Z

167.201.243.136: Added distinguish template

{{Short description|Class of enzymes}}
{{distinguish|peptide alpha-N-acetyltransferase}}
{{enzyme
| Name = Arylamine N-acetyltransferase 2
| EC_number = 2.3.1.5
| CAS_number =
| IUBMB_EC_number =
| GO_code =
| image = Human NAT2.jpg
| width =
| caption = A 3d cartoon depiction of human N-acetyltransferase 2
}}'''''N''-acetyltransferase''' ('''NAT''') is an [[enzyme]] that [[catalysis|catalyzes]] the transfer of [[acetyl]] groups from [[acetyl-CoA]] to [[arylamine]]s, arylhydroxylamines and arylhydrazines.<ref name="pmid2664821">{{cite journal|author=Evans DA|year=1989|title=N-acetyltransferase|journal=Pharmacology & Therapeutics|volume=42|issue=2|pages=157–234|doi=10.1016/0163-7258(89)90036-3|pmid=2664821}}</ref><ref name="ghoshdastider">{{cite journal|vauthors=Ma Y, Ghoshdastider U, Wang J, Ye W, Dötsch V, Filipek S, Bernhard F, Wang X|year=2012|title=Cell-free expression of human glucosamine 6-phosphate N-acetyltransferase (HsGNA1) for inhibitor screening|journal=Protein Expr. Purif.|volume=86|issue=2|pages=120–6|doi=10.1016/j.pep.2012.09.011|pmid=23036358}}</ref><ref name=":8">{{Cite journal|last1=Sim|first1=Edith|last2=Lack|first2=Nathan|last3=Wang|first3=Chan-Ju|display-authors=etal|author1-link=Edith Sim|date=May 2008|title=Arylamine N-acetyltransferases: Structural and functional implications of polymorphisms|journal=Toxicology|volume=254|issue=3|pages=170–183|doi=10.1016/j.tox.2008.08.022|pmid=18852012}}</ref> They have wide specificity for [[aromatic amine]]s, particularly [[serotonin]], and can also catalyze acetyl transfer between arylamines without CoA. ''N''-acetyltransferases are cytosolic enzymes found in the liver and many tissues of most mammalian species, except the [[dog]] and [[fox]], which cannot acetylate [[xenobiotic]]s.<ref name=":0">{{Cite book|title=Casarett and Doull's Toxicology: The Basic Science of Poisons 7th Ed|last=Klaassen|first=Curtis D.|publisher=McGraw-Hill|year=2008|isbn=978-0071470513}}</ref>

[[Acetyl group]]s are important in the conjugation of metabolites from the liver, to allow excretion of the byproducts ([[phase II metabolism]]). This is especially important in the metabolism and excretion of drug products ([[drug metabolism]]). __TOC__

== Enzyme mechanism ==
NAT enzymes are differentiated by the presence of a conserved [[catalytic triad]] that favors [[aromatic amine]] and [[hydrazine]] substrates.<ref name=":1">{{Cite journal|last1=Minchin|first1=Rodney F.|last2=Neville|first2=Butcher J.|date=April 2015|title=The role of lysine100 in the binding of acetylcoenzyme A to human arylamine N-acetyltransferase 1: Implications for other acetyltransferases|journal=Biochemical Pharmacology|volume=94|issue=3|pages=195–202|doi=10.1016/j.bcp.2015.01.015|pmid=25660616|url=https://espace.library.uq.edu.au/view/UQ:352841/UQ352841_OA.pdf}}</ref><ref>{{Cite journal|last1=Weber|first1=W.W.|last2=Cohen|first2=S.N.|last3=Steinberg|first3=M.S.|date=1968|title=Purification and properties of N-acetyltransferase from mammalian liver|journal=Ann N Y Acad Sci|volume=151|issue=2|pages=734–741|doi=10.1111/j.1749-6632.1968.tb11934.x|pmid=4984197|s2cid=44602517}}</ref> NATs catalyze the [[acetylation]] of small molecules through a double displacement reaction called the [[Enzyme kinetics#Ping–pong mechanisms|ping pong]] bi bi reaction.<ref name=":1" /> The [[Reaction mechanism|mechanism]] consists of two sequential reactions.<ref name=":1" /> In reaction one acetyl-CoA initially binds to the enzyme and acetylates Cys68.<ref name=":1" /> In reaction two, after [[acetyl-CoA]] is released, the acetyl acceptor interacts with the acetylated enzyme to form product.<ref name=":1" /> This second reaction is independent of the acetyl donor since it leaves the enzyme before the acetyl acceptor binds.<ref name=":1" /> However, like with many ping pong bi bi reactions, its possible there is competition between the acetyl donor and acetyl acceptor for the unacetylated enzyme.<ref name=":1" /> This leads to substrate-dependent inhibition at high concentrations.<ref name=":1" />

[[File:Mechanism of N-acetyltransferase.png|thumb|center|upright=2| Depiction of the N-acetyltransfersase enzyme mechanism.<ref name=":7" />]]

== Enzyme structure ==
[[File:NAT catalytic triad.png|thumb|left|upright=1.75| 3D depiction of NAT2 active site and catalytic triad.<ref>{{Cite journal|last1=Sinclair|first1=J.C.|last2=Sandy|first2=J.|last3=Delgoda|first3=R.|last4=Sim|first4=E.|last5=Noble|first5=M.E.|author4-link=Edith Sim|date=2000|title=Structure of arylamine N-acetyltransferase reveals a catalytic triad|journal=Nature Structural Biology|volume=7|issue=7|pages=560–564|doi=10.1038/76783|pmid=10876241|s2cid=23694257}}</ref>]]The two NAT enzymes in humans are [[N-acetyltransferase 1|NAT1]] and [[N-acetyltransferase 2|NAT2]].<ref name=":0" /> Mice and rats express three enzymes, NAT1, NAT2, and NAT3.<ref name=":0" /> NAT1 and NAT2 have been found to be closely related in species examined thus far, since the two enzymes share 75-95% of their [[Protein primary structure|amino acid sequence]].<ref name=":2">{{Cite journal|last1=Grant|first1=D.M.|last2=Blum|first2=M.|last3=Meyer|first3=U.A.|date=1992|title=Polymorphisms of N-acetyltransferase genes|journal=Xenobiotica|volume=22|issue=9–10|pages=1073–1081|doi=10.3109/00498259209051861|pmid=1441598}}</ref><ref name=":3">{{Cite journal|last1=Vatsis|first1=K.P.|last2=Weber|first2=W.W.|last3=Bell|first3=D.A.|date=1995|title=Nomenclature for N-acetyltransferases|journal=Pharmacogenetics|volume=5|issue=1|pages=1–17|doi=10.1097/00008571-199502000-00001|pmid=7773298}}</ref> Both also have an [[active site]] [[cysteine]] residue (Cys68) in the N-terminal region.<ref name=":2" /><ref name=":3" /> Further, all functional NAT enzymes contain a triad of catalytically essential residues made up of this [[cysteine]], [[histidine]], and [[asparagine]].<ref name=":7">{{Cite journal|last1=Westwood|first1=I.M.|last2=Kawamura|first2=A.|last3=Fullam|first3=E.|display-authors=etal|date=2006|title=Structure and Mechanism of Arylamine N-Acetyltransferases|journal=Current Topics in Medicinal Chemistry|volume=6|issue=15|pages=1641–1654|doi=10.2174/156802606778108979|pmid=16918475}}</ref> It has been hypothesized that the catalytic effects of the [[breast cancer]] drug [[Cisplatin]] are related to Cys68.<ref name=":4">{{Cite journal|last1=Ragunathan|first1=Nilusha|last2=Dairou|first2=Julien|last3=Pulvinage|first3=Benjamin|display-authors=etal|date=June 2008|title=Identification of the Xenobiotic-Metabolizing Enzyme Arylamine N-Acetyltransferase 1 as a New Target of Cisplatin in Breast Cancer Cells: Molecular and Cellular Mechanisms of Inhibition|journal=Molecular Pharmacology|volume=73|issue=6|pages=1761–1768|doi=10.1124/mol.108.045328|pmid=18310302|s2cid=9214220}}</ref> The inactivation of NAT1 by Cisplatin is caused by an irreversible formation of a Cisplatin adduct with the [[Active site|active-site]] cysteine residue.<ref name=":4" /> The C-terminus helps bind acetyl CoA and differs among NATs including prokaryotic homologues.<ref>{{Cite journal|last1=Sim|first1=E.|last2=Abuhammad|first2=A.|last3=Ryan|first3=A.|author1-link=Edith Sim|date=May 2014|title=Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery|journal=Br J Pharmacol|volume=171|issue=11|pages=2705–2725|doi=10.1111/bph.12598|pmid=24467436|pmc=4158862}}</ref>

NAT1 and NAT2 have different but overlapping substrate specificities.<ref name=":0" /> Human NAT1 preferentially acetylates [[4-Aminobenzoic acid|4-aminobenzoic acid]] (PABA), [[4-Aminosalicylic acid|4 amino salicylic acid]], [[sulfamethoxazole]], and [[sulfanilamide]].<ref name=":0" /> Human NAT2 preferentially acetylates [[isoniazid]] (treatment for [[tuberculosis]]), [[hydralazine]], [[procainamide]], [[dapsone]], [[aminoglutethimide]], and [[Sulfadimidine|sulfamethazine]].<ref name=":0" />

== Biological significance ==
NAT2 is involved in the [[metabolism]] of [[xenobiotic]]s, which can lead to both the inactivation of [[drug]]s and formation of toxic [[metabolite]]s that can be [[carcinogen]]ic.<ref name=":5">{{Cite book|title=Arylamine N-Acetyltransferases in Health and Disease: From Pharmacogenetics to Drug Discovery and Diagnostics|last1=Laureri|first1=Nicola|last2=Sim|first2=Edith|author2-link=Edith Sim|publisher=World Scientific|year=2018|isbn=9789813232006}}</ref> The [[biotransformation]] of xenobiotics may occur in three phases.<ref name=":5" /> In phase I, reactive and polar groups are introduced into the substrates. In phase II, conjugation of xenobiotics with charged species occurs, and in phase III additional modifications are made, with efflux mechanisms leading to excretion by transporters.<ref name=":5" /> A [[genome-wide association study]] (GWAS) identified human NAT2 as the top signal for [[insulin resistance]], a key marker of [[Diabetes mellitus|diabetes]] and a major cardiovascular risk factor<ref name=":5" /> and has been shown to be associated with whole-body insulin resistance in NAT1 [[Knockout mouse|knockout mice]].<ref>{{Cite journal|last1=Camporez|first1=João Paulo|last2=Wang|first2=Yongliang|last3=Faarkrog|first3=Kasper|display-authors=etal|date=Dec 2017|title=Mechanism by which arylamine N-acetyltransferase 1 ablation causes insulin resistance in mice|journal=PNAS|volume=114|issue=52|pages=E11285–E11292|doi=10.1073/pnas.1716990115|pmid=29237750|pmc=5748223|doi-access=free}}</ref> NAT1 is thought to have an [[Endogeny (biology)|endogenous]] role, likely linked to fundamental cellular metabolism.<ref name=":5" /> This may be related to why NAT1 is more widely distributed among tissues than NAT2.<ref name=":5" />

== Importance in humans ==
Each individual metabolizes xenobiotics at different rates, resulting from polymorphisms of the xenobiotic metabolism [[gene]]s.<ref name=":5" /> Both NAT1 and NAT2 are encoded by two highly polymorphic genes located on [[chromosome 8]].<ref name=":0" /> NAT2 [[Polymorphism (biology)|polymorphisms]] were one of the first variations to explain this inter-individual variability for [[drug metabolism]].<ref>{{Cite journal|last=McDonagh|first=E.M.|display-authors=etal|date=2014|title=PharmGKB summary: very important pharmacogene infor- mation for N-acetyltransferase 2|journal=Pharmacogenet. Genomics|volume=24|issue=8|pages=409–425|doi=10.1097/FPC.0000000000000062|pmid=24892773|pmc=4109976}}</ref> These polymorphisms modify the stability and/ or catalytic activity of enzymes that alter acetylation rates for drugs and xenobiotics, a trait called acetylator [[phenotype]].<ref>{{Cite journal|last1=Evans|first1=D.A.|last2=White|first2=T.A.|date=1964|title=Human acetylation polymorphism|journal=J. Lab. Clin. Med.|volume=63|pages=394–403|pmid=14164493}}</ref> For NAT2, the acetylator phenotype is described as either slow, intermediate, or rapid.<ref>{{Cite journal|last1=Hein|first1=D.W.|last2=Doll|first2=M.A.|date=2012|title=Accuracy of various human NAT2 SNP genotyping panels to infer rapid, intermediate and slow acetylator phenotypes.|journal=Pharmacogenomics|volume=13|issue=1|pages=31–41|doi=10.2217/pgs.11.122|pmid=22092036|pmc=3285565}}</ref> Beyond modifying enzymatic activity, [[epidemiological studies]] have found an association of NAT2 polymorphisms with various cancers, likely from varying environmental [[carcinogen]]s.<ref name=":5" />

Indeed, NAT2 is highly polymorphic in several human populations.<ref name=":6">{{Cite journal|last1=Rajasekaran|first1=M.|last2=Abirami|first2=Santhanam|last3=Chen|first3=Chinpan|date=2011|title=Effects of Single Nucleotide Polymorphisms on Human N-Acetyltransferase 2 Structure and Dynamics by Molecular Dynamics Simulation|doi=10.1371/journal.pone.0025801 |journal=PLOS ONE|volume=6|issue=9|pages=e25801|pmid=21980537|pmc=3183086|bibcode=2011PLoSO...625801R|doi-access=free}}</ref> Polymorphisms of NAT2 include the single amino acid substitutions R64Q, I114T, D122N, L137F, Q145P, R197Q, and G286E.<ref name=":6" /> These are classified as slow acetylators, while the wild-type NAT2 is classified as a fast acetylator.<ref name=":6" /> Slow acetylators tend to be associated with drug toxicity and cancer susceptibility.<ref name=":6" /> For instance, the NAT2 slow acetylator genotype is associated with an increased risk of [[bladder cancer]], especially among cigarette smokers.<ref>{{Cite journal|last=Hein|first=D.W.|date=2000|title=Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms.|journal=Cancer Epidemiol. Biomarkers Prev.|volume=9|issue=1|pages=29–42|pmid=10667461}}</ref> [[Single-nucleotide polymorphism|Single nucleotide polymorphisms]] (SNPs) of NAT1 include R64W, V149I, R187Q, M205V, S214A, D251V, E26K, and I263V, and are related to [[genetic predisposition]] to [[cancer]], [[birth defect]]s, and other diseases.<ref>{{Cite journal|last1=Walraven|first1=Jason M.|last2=Trent|first2=John O.|last3=Hein|first3=David W.|date=2008|title=Structure-Function Analysis of Single Nucleotide Polymorphisms in Human N-Acetyltransferase 1|journal=Drug Metabolism Reviews|volume=40|issue=1|pages=169–184|via=Informa Healthcare|doi=10.1080/03602530701852917|pmid=18259988|pmc=2265210}}</ref> The effect of the slow acetylator SNPs in the [[coding region]] predominantly act through creating an unstable protein that aggregates intracellularly prior to [[ubiquitination]] and degradation.<ref name=":8" />

50% of the British population are deficient in hepatic ''N''-acetyltransferase. This is known as a negative acetylator status. Drugs affected by this are:
* isoniazid
* procainamide
* hydralazine
* dapsone
* sulfasalazine

Adverse events from this deficiency include [[peripheral neuropathy]] and [[Hepatotoxicity|hepatoxicity]].<ref>{{Cite journal|last1=Unissa|first1=Ameeruddin Nusrath|last2=Subbian|first2=Selvakumar|last3=Hanna|first3=Luke Elizabeth|last4=Selvakumar|first4=Nagamiah|date=2016|title=Overview on mechanisms of isoniazid action and resistance in Mycobacterium tuberculosis|journal=Infection, Genetics and Evolution|volume=45|pages=474–492|doi=10.1016/j.meegid.2016.09.004|pmid=27612406}}</ref> The slowest acetylator [[haplotype]], ''NAT2*5B'' (strongest association with [[bladder cancer]]), seems to have been selected for in the last 6,500 years in western and central Eurasian people, suggesting slow acetylation gave an evolutionary advantage to this population, despite the recent unfavorable epidemiological health outcomes data.<ref>{{Cite journal|last1=Patin|first1=E.|last2=Barreiro|first2=L.B.|last3=Sabeti|first3=P.C.|display-authors=etal|date=2006|title=Deciphering the ancient and complex evolutionary history of human arylamine N-acetyltransferase genes|journal=Am J Hum Genet|volume=78|issue=3|pages=423–436|doi=10.1086/500614|pmid=16416399|pmc=1380286}}</ref>

==Examples==

The following is a list of human [[gene]]s that encode N-acetyltransferase enzymes:
{| class="wikitable" border="1"
|-
! Symbol
! Name
|-
| ''[[Aralkylamine N-acetyltransferase|AANAT]]''
| aralkylamine N-acetyltransferase
|-
| ''[[ARD1A]]''
| ARD1 homolog A, N-acetyltransferase (S. cerevisiae)
|-
| ''[[GNPNAT1]]''
| glucosamine-phosphate N-acetyltransferase 1
|-
| ''[[HGSNAT]]''
| heparan-alpha-glucosaminide N-acetyltransferase
|-
| ''[[MAK10]]''
| MAK10 homolog, amino-acid N-acetyltransferase subunit (S. cerevisiae)
|-
| ''[[NAT1]]''
| N-acetyltransferase 1 (arylamine N-acetyltransferase)
|-
| ''[[N-acetyltransferase 2|NAT2]]''
| N-acetyltransferase 2 (arylamine N-acetyltransferase)
|-
| ''[[NAT5]]''
| N-acetyltransferase 5 (GCN5-related, putative)
|-
| ''[[NAT6]]''
| N-acetyltransferase 6 (GCN5-related)
|-
| ''[[NAT8]]''
| N-acetyltransferase 8 (GCN5-related, putative)
|-
| ''[[NAT8L]]''
| N-acetyltransferase 8-like (GCN5-related, putative)
|-
| ''[[NAT9]]''
| N-acetyltransferase 9 (GCN5-related, putative)
|-
| ''[[NAT10]]''
| N-acetyltransferase 10 (GCN5-related)
|-
| ''[[NAT11]]''
| N-acetyltransferase 11 (GCN5-related, putative)
|-
| ''[[NAT12]]''
| N-acetyltransferase 12 (GCN5-related, putative)
|-
| ''[[NAT13]]''
| N-acetyltransferase 13 (GCN5-related)
|-
| ''[[NAT14]]''
| N-acetyltransferase 14 (GCN5-related, putative)
|-
| ''[[NAT15]]''
| N-acetyltransferase 15 (GCN5-related, putative)
|}

== References ==
{{Reflist}}{{Acyltransferases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

[[Category:EC 2.3.1]]

Carbohydrate-responsive element-binding protein

2024-05-09T16:48:32Z

167.201.243.136: /* Role in glycolysis */ Added unsourced section template

{{Short description|Protein found in humans}}
{{Infobox_gene}}
'''Carbohydrate-responsive element-binding protein''' ('''ChREBP''') also known as '''MLX-interacting protein-like''' (MLXIPL) is a [[protein]] that in humans is encoded by the ''MLXIPL'' [[gene]].<ref name="pmid9860302">{{cite journal | vauthors = Meng X, Lu X, Li Z, Green ED, Massa H, Trask BJ, Morris CA, Keating MT | display-authors = 6 | title = Complete physical map of the common deletion region in Williams syndrome and identification and characterization of three novel genes | journal = Human Genetics | volume = 103 | issue = 5 | pages = 590–599 | date = November 1998 | pmid = 9860302 | doi = 10.1007/s004390050874 | s2cid = 23530406 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: MLXIPL MLX interacting protein-like| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51085}}</ref> The protein name derives from the protein's interaction with carbohydrate response element sequences of DNA.

== Function ==
[[File:ChREBP.png|thumb|320x320px|Domains of ChREBP. The N-terminal glucose-sensing module consists of the low glucose inhibitory domain (LID) and the glucose activated conserved element (GRACE). The C-terminal regions consists of a polyproline-rich, a bHLH/LZ and a leucine-zipper-like (Zip-like) domain. Phosphorylation sites in red, acetylation sites in blue and O-GlcNAcylation sites in green.<ref name="Ortega-Prieto_2019" />]]
This gene encodes a [[basic helix-loop-helix]] leucine zipper [[transcription factor]] of the [[Myc]] / [[MAX (gene)|Max]] / [[MXD1|Mad]] superfamily. This protein forms a heterodimeric complex and binds and activates, in a glucose-dependent manner, [[carbohydrate response element]] (ChoRE) motifs in the promoters of [[triglyceride]] synthesis genes.<ref name="entrez"/>

ChREBP is activated by glucose, independent of [[insulin]].<ref name="pmid24222088">{{cite journal | vauthors = Xu X, So JS, Park JG, Lee AH | title = Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP | journal = Seminars in Liver Disease | volume = 33 | issue = 4 | pages = 301–311 | date = November 2013 | pmid = 24222088 | pmc = 4035704 | doi = 10.1055/s-0033-1358523 }}</ref> In [[adipose tissue]], ChREBP induces [[De novo synthesis|de novo]] [[lipogenesis]] from glucose in response to a glucose flux into [[adipocyte]]s.<ref name="pmid23443243">{{cite journal | vauthors = Czech MP, Tencerova M, Pedersen DJ, Aouadi M | title = Insulin signalling mechanisms for triacylglycerol storage | journal = Diabetologia | volume = 56 | issue = 5 | pages = 949–964 | date = May 2013 | pmid = 23443243 | pmc = 3652374 | doi = 10.1007/s00125-013-2869-1 }}</ref><ref name="pmid24222088" /> In the liver, glucose induction of ChREBP promotes [[glycolysis]] and [[lipogenesis]].<ref name="pmid24222088" />

== Clinical significance ==

This gene is deleted in [[Williams syndrome|Williams-Beuren syndrome]], a multisystem developmental disorder caused by the deletion of contiguous genes at chromosome 7q11.23.<ref name="entrez"/>

Excess expression of ChREBP in the liver due to [[metabolic syndrome]] or [[type 2 diabetes]] can lead to [[steatosis]] in the liver.<ref name="pmid24222088" /> In [[non-alcoholic fatty liver disease]], about 25% of total liver [[lipid]]s result from [[de novo synthesis]] (synthesis of lipids from glucose).<ref name="Ortega-Prieto_2019">{{cite journal | vauthors = Ortega-Prieto P, Postic C | title = Carbohydrate Sensing Through the Transcription Factor ChREBP | journal = Frontiers in Genetics | volume = 10 | pages = 472 | year = 2019 | pmid = 31275349 | pmc = 6593282 | doi = 10.3389/fgene.2019.00472 | doi-access = free }}</ref> High blood glucose and insulin enhance [[lipogenesis]] in the liver by activation of ChREBP and [[Sterol regulatory element-binding protein 1|SREBP-1c]], respectively.<ref name="Ortega-Prieto_2019" />

Chronically elevated blood glucose can activate ChREBP in the [[pancreas]] can lead to excessive lipid synthesis in [[beta cell]]s, increasing lipid accumulation in those cells, leading to [[lipotoxicity]], beta-cell [[apoptosis]], and type 2 diabetes.<ref name="pmid31623194 ">{{cite journal | vauthors = Song Z, Yang H, Zhou L, Yang F | title = Glucose-Sensing Transcription Factor MondoA/ChREBP as Targets for Type 2 Diabetes: Opportunities and Challenges | journal = International Journal of Molecular Sciences | volume = 20 | issue = 20 | pages = E5132 | date = October 2019 | pmid = 31623194 | pmc = 6829382 | doi = 10.3390/ijms20205132 | doi-access = free }}</ref>

== Interactions ==

MLXIPL has been shown to [[Protein-protein interaction|interact]] with [[MLX (gene)|MLX]].<ref name="pmid11230181">{{cite journal | vauthors = Cairo S, Merla G, Urbinati F, Ballabio A, Reymond A | title = WBSCR14, a gene mapping to the Williams--Beuren syndrome deleted region, is a new member of the Mlx transcription factor network | journal = Human Molecular Genetics | volume = 10 | issue = 6 | pages = 617–627 | date = March 2001 | pmid = 11230181 | doi = 10.1093/hmg/10.6.617 | doi-access = free }}</ref>

== Role in glycolysis ==
{{unsourced|section|date=May 2024}}
ChREBP is translocated to the nucleus and binds to DNA after dephosphorylation of a p-Ser and a p-Thr residue by [[PP2A]], which itself is activated by [[xylulose-5-phosphate]]. Xu5p is produced in the [[pentose phosphate pathway]] when levels of [[Glucose-6-phosphate]] are high (the cell has ample glucose). In the liver, ChREBP mediates activation of several regulatory enzymes of glycolysis and lipogenesis including L-type pyruvate kinase (L-PK), acetyl CoA carboxylase, and fatty acid synthase.

== References ==
{{reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = de Luis O, Valero MC, Jurado LA | title = WBSCR14, a putative transcription factor gene deleted in Williams-Beuren syndrome: complete characterisation of the human gene and the mouse ortholog | journal = European Journal of Human Genetics | volume = 8 | issue = 3 | pages = 215–222 | date = March 2000 | pmid = 10780788 | doi = 10.1038/sj.ejhg.5200435 | doi-access = free }}
* {{cite journal | vauthors = Kawaguchi T, Takenoshita M, Kabashima T, Uyeda K | title = Glucose and cAMP regulate the L-type pyruvate kinase gene by phosphorylation/dephosphorylation of the carbohydrate response element binding protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 24 | pages = 13710–13715 | date = November 2001 | pmid = 11698644 | pmc = 61106 | doi = 10.1073/pnas.231370798 | bibcode = 2001PNAS...9813710K | doi-access = free }}
* {{cite journal | vauthors = Kawaguchi T, Osatomi K, Yamashita H, Kabashima T, Uyeda K | title = Mechanism for fatty acid "sparing" effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase | journal = The Journal of Biological Chemistry | volume = 277 | issue = 6 | pages = 3829–3835 | date = February 2002 | pmid = 11724780 | doi = 10.1074/jbc.M107895200 | doi-access = free }}
* {{cite journal | vauthors = Hillman RT, Green RE, Brenner SE | title = An unappreciated role for RNA surveillance | journal = Genome Biology | volume = 5 | issue = 2 | pages = R8 | year = 2005 | pmid = 14759258 | pmc = 395752 | doi = 10.1186/gb-2004-5-2-r8 | doi-access = free }}
* {{cite journal | vauthors = Merla G, Howald C, Antonarakis SE, Reymond A | title = The subcellular localization of the ChoRE-binding protein, encoded by the Williams-Beuren syndrome critical region gene 14, is regulated by 14-3-3 | journal = Human Molecular Genetics | volume = 13 | issue = 14 | pages = 1505–1514 | date = July 2004 | pmid = 15163635 | doi = 10.1093/hmg/ddh163 | doi-access = free }}
* {{cite journal | vauthors = Li MV, Chang B, Imamura M, Poungvarin N, Chan L | title = Glucose-dependent transcriptional regulation by an evolutionarily conserved glucose-sensing module | journal = Diabetes | volume = 55 | issue = 5 | pages = 1179–1189 | date = May 2006 | pmid = 16644671 | doi = 10.2337/db05-0822 | doi-access = free }}
{{refend}}

{{Transcription factors and intracellular receptors}}
{{gene-7-stub}}

ADH5

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167.201.243.136: /* Clinical significance */ Copy edit

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{cs1 config|name-list-style=vanc}}
{{Infobox_gene}}
'''Alcohol dehydrogenase class-3''' is an [[enzyme]] that in [[human]]s is encoded by the ''ADH5'' [[gene]].<ref name="pmid1446828">{{cite journal | vauthors = Hur MW, Edenberg HJ | title = Cloning and characterization of the ADH5 gene encoding human alcohol dehydrogenase 5, formaldehyde dehydrogenase | journal = Gene | volume = 121 | issue = 2 | pages = 305–11 |date=Dec 1992| pmid = 1446828 | doi =10.1016/0378-1119(92)90135-C }}</ref><ref name="pmid6424546">{{cite journal | vauthors = Adinolfi A, Adinolfi M, Hopkinson DA | title = Immunological and biochemical characterization of the human alcohol dehydrogenase chi-ADH isozyme | journal = Ann Hum Genet | volume = 48 | issue = Pt 1 | pages = 1–10 |date=May 1984| pmid = 6424546 | doi =10.1111/j.1469-1809.1984.tb00828.x | s2cid = 85113864 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: ADH5 alcohol dehydrogenase 5 (class III), chi polypeptide| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=128}}</ref>

This gene encodes [[glutathione]]-dependent [[formaldehyde dehydrogenase]] or the class III [[alcohol dehydrogenase]] chi subunit, which is a member of the [[Alcohol (chemistry)|alcohol]] dehydrogenase family. Members of this family [[metabolism|metabolize]] a wide variety of [[Substrate (chemistry)|substrates]], including [[ethanol]], [[retinol]], other [[Aliphatic compound|aliphatic alcohol]]s, [[hydroxysteroids]], and [[lipid peroxidation]] products. Class III alcohol dehydrogenase is a [[homodimer]] composed of 2 chi subunits. It has virtually no activity for ethanol [[oxidation]], but exhibits high activity for oxidation of long-chain [[primary alcohol]]s and for oxidation of S-hydroxymethyl-glutathione, a spontaneous [[adduct]] between formaldehyde and glutathione.

This enzyme is an important component of [[cellular metabolism]] for the elimination of formaldehyde, a potent irritant and sensitizing agent that causes [[lacrymation]], [[rhinitis]], [[pharyngitis]], and [[contact dermatitis]].<ref name="entrez"/>

==Clinical significance==
Mutations of the ''ADH5'' gene and ''[[ALDH2]]'' gene cause [[AMED syndrome]], an autosomal recessive [[digenic disorder|digenic]] multisystem disorder characterized by global developmental delay with impaired intellectual development, short stature, growth impairment and early development of [[myelodysplastic syndrome]] and bone marrow failure. The syndrome was first described in 2020.<ref>{{cite web|url=https://www.omim.org/entry/619151|title=AMED SYNDROME, DIGENIC; AMEDS|id=#619151|access-date=1 May 2024|last=Kniffin|first=Cassandra L.|date=27 November 2023|orig-date=Originally published on 13 January 2021|website=Online Mendelian Inheritance in Man|publisher=Johns Hopkins University}}</ref>

==References==
{{reflist}}

==Further reading==
{{refbegin | 2}}
*{{cite journal | vauthors=Iborra FJ, Renau-Piqueras J, Portoles M |title=Immunocytochemical and biochemical demonstration of formaldhyde dehydrogenase (class III alcohol dehydrogenase) in the nucleus. |journal=J. Histochem. Cytochem. |volume=40 |issue= 12 |pages= 1865–78 |year= 1992 |pmid= 1453005 |doi= 10.1177/40.12.1453005|display-authors=etal|doi-access=free }}
*{{cite journal | vauthors=Giri PR, Krug JF, Kozak C |title=Cloning and comparative mapping of a human class III (chi) alcohol dehydrogenase cDNA. |journal=Biochem. Biophys. Res. Commun. |volume=164 |issue= 1 |pages= 453–60 |year= 1989 |pmid= 2679557 |doi=10.1016/0006-291X(89)91741-5 |display-authors=etal|url=https://zenodo.org/record/1253802 }}
*{{cite journal | vauthors=Sharma CP, Fox EA, Holmquist B |title=cDNA sequence of human class III alcohol dehydrogenase. |journal=Biochem. Biophys. Res. Commun. |volume=164 |issue= 2 |pages= 631–7 |year= 1989 |pmid= 2818582 |doi=10.1016/0006-291X(89)91507-6 |display-authors=etal}}
*{{cite journal | vauthors=Beisswenger TB, Holmquist B, Vallee BL |title=chi-ADH is the sole alcohol dehydrogenase isozyme of mammalian brains: implications and inferences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=82 |issue= 24 |pages= 8369–73 |year= 1986 |pmid= 2934732 |doi=10.1073/pnas.82.24.8369 | pmc=390917 |doi-access=free }}
*{{cite journal | vauthors=Dafeldecker WP, Vallee BL |title=Organ-specific human alcohol dehydrogenase: isolation and characterization of isozymes from testis. |journal=Biochem. Biophys. Res. Commun. |volume=134 |issue= 3 |pages= 1056–63 |year= 1986 |pmid= 2936344 |doi=10.1016/0006-291X(86)90358-X }}
*{{cite journal | vauthors=Kaiser R, Holmquist B, Hempel J |title=Class III human liver alcohol dehydrogenase: a novel structural type equidistantly related to the class I and class II enzymes. |journal=Biochemistry |volume=27 |issue= 4 |pages= 1132–40 |year= 1988 |pmid= 3365377 |doi=10.1021/bi00404a009 |display-authors=etal}}
*{{cite journal | vauthors=Khokha AM, Voronov PP, Zimatkin SM |title=[Immunoenzyme and immunohistochemical analysis of class III alcohol dehydrogenase from human testis] |journal=Biokhimiia |volume=59 |issue= 7 |pages= 997–1002 |year= 1994 |pmid= 7948423 }}
*{{cite journal | vauthors=Engeland K, Höög JO, Holmquist B |title=Mutation of Arg-115 of human class III alcohol dehydrogenase: a binding site required for formaldehyde dehydrogenase activity and fatty acid activation. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue= 6 |pages= 2491–4 |year= 1993 |pmid= 8460164 |doi=10.1073/pnas.90.6.2491 | pmc=46113 |display-authors=etal|doi-access=free |bibcode=1993PNAS...90.2491E }}
*{{cite journal | vauthors=Holmquist B, Moulis JM, Engeland K, Vallee BL |title=Role of arginine 115 in fatty acid activation and formaldehyde dehydrogenase activity of human class III alcohol dehydrogenase. |journal=Biochemistry |volume=32 |issue= 19 |pages= 5139–44 |year= 1993 |pmid= 8494891 |doi=10.1021/bi00070a024 }}
*{{cite journal | vauthors=Engeland K, Maret W |title=Extrahepatic, differential expression of four classes of human alcohol dehydrogenase. |journal=Biochem. Biophys. Res. Commun. |volume=193 |issue= 1 |pages= 47–53 |year= 1993 |pmid= 8503936 |doi= 10.1006/bbrc.1993.1588 }}
*{{cite journal | vauthors=Yang ZN, Bosron WF, Hurley TD |title=Structure of human chi chi alcohol dehydrogenase: a glutathione-dependent formaldehyde dehydrogenase. |journal=J. Mol. Biol. |volume=265 |issue= 3 |pages= 330–43 |year= 1997 |pmid= 9018047 |doi= 10.1006/jmbi.1996.0731 }}
*{{cite journal | vauthors=Mori O, Haseba T, Kameyama K |title=Histological distribution of class III alcohol dehydrogenase in human brain. |journal=Brain Res. |volume=852 |issue= 1 |pages= 186–90 |year= 2000 |pmid= 10661511 |doi=10.1016/S0006-8993(99)02201-5 |s2cid=23510523 |display-authors=etal}}
*{{cite journal | vauthors=Sanghani PC, Stone CL, Ray BD |title=Kinetic mechanism of human glutathione-dependent formaldehyde dehydrogenase. |journal=Biochemistry |volume=39 |issue= 35 |pages= 10720–9 |year= 2000 |pmid= 10978156 |doi=10.1021/bi9929711 |display-authors=etal}}
*{{cite journal | vauthors=Lee DK, Suh D, Edenberg HJ, Hur MW |title=POZ domain transcription factor, FBI-1, represses transcription of ADH5/FDH by interacting with the zinc finger and interfering with DNA binding activity of Sp1. |journal=J. Biol. Chem. |volume=277 |issue= 30 |pages= 26761–8 |year= 2002 |pmid= 12004059 |doi= 10.1074/jbc.M202078200 |doi-access= free }}
*{{cite journal | vauthors=Jelski W, Chrostek L, Szmitkowski M, Laszewicz W |title=Activity of class I, II, III, and IV alcohol dehydrogenase isoenzymes in human gastric mucosa. |journal=Dig. Dis. Sci. |volume=47 |issue= 7 |pages= 1554–7 |year= 2002 |pmid= 12141816 |doi=10.1023/A:1015871219922 |s2cid=31197228 }}
*{{cite journal | vauthors=Sanghani PC, Robinson H, Bosron WF, Hurley TD |title=Human glutathione-dependent formaldehyde dehydrogenase. Structures of apo, binary, and inhibitory ternary complexes. |journal=Biochemistry |volume=41 |issue= 35 |pages= 10778–86 |year= 2002 |pmid= 12196016 |doi=10.1021/bi0257639 }}
*{{cite journal | vauthors=Strausberg RL, Feingold EA, Grouse LH |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |bibcode=2002PNAS...9916899M |display-authors=etal|doi-access=free }}
*{{cite journal | vauthors=Sanghani PC, Bosron WF, Hurley TD |title=Human glutathione-dependent formaldehyde dehydrogenase. Structural changes associated with ternary complex formation. |journal=Biochemistry |volume=41 |issue= 51 |pages= 15189–94 |year= 2003 |pmid= 12484756 |doi=10.1021/bi026705q }}
{{refend}}

==External links==
* {{UCSC gene info|ADH5}}
{{PDB Gallery|geneid=128}}

{{protein-stub}}

Microsomal ethanol oxidizing system

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167.201.243.136: Added page number needed flag

{{Short description|Alternate ethanol oxidizing system in human metabolism}}
{{other uses|Meos (disambiguation)}}

The '''microsomal ethanol oxidizing system''' (MEOS) is an alternate pathway of [[ethanol]] metabolism that occurs in the [[smooth endoplasmic reticulum]] in the oxidation of ethanol to [[acetaldehyde]]. While playing only a minor role in ethanol metabolism in average individuals, MEOS activity increases after chronic alcohol consumption. The MEOS pathway requires the [[CYP2E1]] enzyme, part of the [[cytochrome P450]] family of enzymes, to convert ethanol to [[acetaldehyde]]. Ethanol’s affinity for CYP2E1 is lower than its affinity for [[alcohol dehydrogenase]]. It has delayed activity in non-chronic alcohol consumption states as increase in MEOS activity is correlated with an increase in production of [[CYP2E1]], seen most conclusively in alcohol dehydrogenase negative deer mice.<ref name="discovery">Chales S. Lieber. 2004. The Discovery of the Microsomal Ethanol Oxidizing System and Its Physiologic and Pathologic Role. ''Drug Metabolism Reviews'' 36:511-529.</ref>

The MEOS pathway converts ethanol to acetaldehyde by way of a [[redox reaction]]. In this reaction, ethanol is oxidized (losing two hydrogens) and [[Oxygen|O2]] is reduced (by accepting hydrogen) to form [[Water|H2O]]. NADPH is used as donor of hydrogen, forming NADP+.<ref>Robbins and Cotran: Pathologic basis of disease (8th edition)</ref>{{page number needed|date=May 2024}} This process consumes ATP and dissipates heat, thus leading to the hypothesis that long term drinkers see an increase in resting energy expenditure.<ref>Francisco Santolaria and Emilio González-
Reimers. 2003. Alcohol and Nutrition: an
Integrated Perspective in ''Nutrition and Alcohol: Linking Nutrient Interactions and Dietary Intake''. p. 5 Ronald Ross Watson and Victor R. Preedy (eds). Taylor and Francis, CRC Press.</ref>

The increase in rest energy expenditure has, according to some studies, been explained by indicating that the MEOS "expends" nine calories per gram of ethanol to metabolize versus 7 calories per gram of ethanol ingested. This results in a net loss of 2 calories per gram of ethanol ingested.

==References==
<references/>

[[Category:Metabolic pathways]]

PTPN1

2024-04-24T21:47:04Z

167.201.243.136: Copy editing per MOS:HEADINGS

{{cs1 config|name-list-style=vanc}}
{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Tyrosine-protein phosphatase non-receptor type 1''' also known as '''protein-tyrosine phosphatase 1B''' (PTP1B) is an [[enzyme]] that is the founding member of the [[protein tyrosine phosphatase]] (PTP) family. In humans it is encoded by the ''PTPN1'' [[gene]].<ref name="pmid2164224"/> PTP1B is a negative regulator of the insulin signaling pathway and is considered a promising potential therapeutic target, in particular for treatment of [[type 2 diabetes]].<ref name="Combs2010"/> It has also been implicated in the development of breast cancer and has been explored as a potential therapeutic target in that avenue as well.<ref name="pmid19782770"/><ref name="pmid17347513"/><ref name="pmid17259984"/>

== Structure and function ==

PTP1B was first isolated from a human placental protein extract,<ref name="tonkspur"/><ref name="tonkschar"/> but it is expressed in many tissues.<ref name="Chernoff_1990"/> PTP1B is localized to the cytoplasmic face of the [[endoplasmic reticulum]].<ref name="Frangioni_1992"/> PTP1B can dephosphorylate the phosphotyrosine residues of the activated [[insulin receptor]] kinase.<ref name="tonkschar" /><ref name="Cicirelli_1990"/><ref name="Seely_1996"/> In mice, genetic ablation of PTPN1 results in enhanced insulin sensitivity.<ref name="Elchebly_1999"/><ref name="Klaman_2000"/> Several other tyrosine kinases, including [[epidermal growth factor receptor]],<ref name="Flint_1997"/> [[insulin-like growth factor 1 receptor]],<ref name="Buckley_2002"/> [[colony stimulating factor 1 receptor]],<ref name="Heinonen_2006"/> [[Src (gene)|c-Src]],<ref name="Zhu_2007"/> [[Janus kinase 2]],<ref name="Myers_2001"/> [[TYK2]],<ref name="Myers_2001"/> and [[focal adhesion kinase]]<ref name="Zhang_2006"/> as well as other tyrosine-phosphorylated proteins, including [[BCAR1]],<ref name="Liu_1996"/> [[DOK1]],<ref name="Dubé_2004"/> [[beta-catenin]]<ref name="Balsamo_1998"/> and [[cortactin]]<ref name="Stuible_2008"/> have also been described as PTP1B substrates.

The first crystal structure of the PTP1B catalytic domain revealed that the catalytic site exists within a deep cleft of the protein formed by three loops including the WPD loop with the Asp181 residue, a pTyr loop with the Tyr46 residue and a Q loop with the Gln262 residue.<ref name="Tonks_2003"/><ref name="pmid8128219"/> The pTyr loop and Tyr46 residue are located on the surface of the protein, and thus help to determine the depth a substrate can obtain within the cleft. This acts as a means of driving selectivity, as substrates containing smaller phosphoresidues cannot reach the site of catalytic activity at the base of the cleft.<ref name="Tonks_2003"/> Upon substrate binding, PTP1B undergoes a structural modification in which the WPD loop closes around the substrate, introducing stabilizing [[pi stacking]] interactions between the aromatic rings of the [[phosphotyrosine]] (pTyr) substrate residue and the Phe182 residue on the WPD loop.<ref name="pmid8128219"/>

== Mechanism ==

The phosphatase activity of PTP1B occurs via a two-step mechanism.<ref name="Tonks_2003"/> The dephosphorylation of the pTyr substrate occurs in the first step, while the enzyme intermediates are broken down during the second step. During the first step, there is a nucleophilic attack at the phosphocenter by the reduced Cys215 residue, followed by subsequent protonation by Asp181 to yield the neutral [[tyrosine]] phenol. The active enzyme is regenerated after the thiophosphate intermediate is hydrolyzed, which is facilitated by the [[hydrogen bonding]] interactions of Gln262 and Asp181 that help to position in the water molecule at the desired site of nucleophillic attack.

[[File:PTP1B Mechanism.png|thumb|center|upright=3|alt=Arrow pushing mechanism of PTP1B phosphatase activity. |Two step mechanism of PTP1B phosphatase activity.]]

== Regulation ==

The Cys215 residue is essential for the enzymatic activity of PTP1B and similar cysteine residues are required for the activity of other members of the Class I [[Protein tyrosine phosphatase|PTP]] family.<ref name="pmid15186772"/> The thiolate anion form is needed for nucleophilic activity but it is susceptible to oxidation by [[reactive oxygen species]] (ROS) in the cell which would render the enzyme non-functional. This cysteine residue has been shown to oxidize under increased cellular concentrations of [[hydrogen peroxide]] (H2O2), produced in response to [[Epidermal growth factor|EGF]] and [[insulin]] signaling.<ref name="pmid11297536"/><ref name="pmid9624118"/><ref name="sundaresan_1995"/> The thiolate is oxidized to a [[sulfenic acid]], which is converted to a sulfenyl amide after reacting with the adjacent Ser216 residue.<ref name="pmid12802338 "/> This modification of the Cys215 residue prevents further oxidation of the residue which would be irreversible, and also induces a structural change in the cleft of the active site such that substrates may not bind.<ref name="pmid12802338 "/><ref name="pmid12802339"/> This oxidation can be reversed through reduction by [[glutathione]] and acts as a means of regulating PTP1B activity.<ref name="pmid12802339"/> Phosphorylation of the Ser50 residue has also been shown as a point of allosteric regulation of PTP1B, in which the phosphorylated state of the enzyme is inactive.<ref name="pmid11579209"/>

== Interactions ==

PTPN1 has been shown to [[Protein-protein interaction|interact]] with [[BCAR1]],<ref name="Liu_1996"/> [[epidermal growth factor receptor]],<ref name="pmid10889023"/><ref name="pmid8621392"/> [[Grb2]]<ref name="Liu_1996"/><ref name="pmid10660596"/> and [[IRS1]].<ref name="pmid11579209"/><ref name=pmid10660596/> [[Kinase insert domain receptor|Vascular endothelial growth factor Receptor-2]]<ref>{{cite journal | vauthors = Lanahan AA, Lech D, Dubrac A, Zhang J, Zhuang ZW, Eichmann A, Simons M | title = PTP1b is a physiologic regulator of vascular endothelial growth factor signaling in endothelial cells | journal = Circulation | volume = 130 | issue = 11 | pages = 902–9 | date = September 2014 | pmid = 24982127 | doi = 10.1161/CIRCULATIONAHA.114.009683 | pmc = 6060619 }}</ref> and [[Vascular endothelial growth factor A|Vascular endothelial growth factor]] via [[PPARGC1A|PGC1-alpha]]/[[Estrogen-related receptor alpha|ERR-alpha]]<ref>{{cite journal | vauthors = Figueiredo H, Figueroa AL, Garcia A, Fernandez-Ruiz R, Broca C, Wojtusciszyn A, Malpique R, Gasa R, Gomis R | display-authors = 6 | title = Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes | journal = Science Translational Medicine | volume = 11 | issue = 497 | pages = eaar6294 | date = June 2019 | pmid = 31217339 | doi = 10.1126/scitranslmed.aar6294 | hdl = 10609/103266 | s2cid = 195188512 | hdl-access = free }}</ref>

== Clinical significance ==

PTP1B has clinical implications in the treatment of [[type 2 diabetes]] as well as cancer. Gene knockout studies conducted in murine models has provided substantial evidence for the role PTP1B plays in the regulation of [[insulin]] signalling and the development of [[obesity]].<ref name="Elchebly_1999"/><ref name="Klaman_2000"/> PTPN1 knockout mice kept on high fat diets showed a resistance to [[obesity]] and an increased degree of [[insulin]] sensitivity as compared to their [[wild-type]] counterparts.<ref name="Elchebly_1999"/><ref name="Klaman_2000"/> As such, the design and development of PTP1B inhibitors is a growing field of research for the treatment of [[type 2 diabetes]] and [[obesity]].<ref name="pmid20814956"/>

Although PTP1B is generally studied as a regulator of metabolism, some research suggest it may have a role in tumor development, though whether it is oncogenic or tumor suppressive is unclear, as there is data in support of both arguments. The high ROS concentrations within cancer cells provide an environment for potential constitutive inactivation of PTP1B and it has been shown in two human cancer cell lines [[HepG2]] and [[A431 cells|A431]], that up to 40% of the Cys215 residues in PTP1B can be selectively irreversibly oxidized under these cellular conditions resulting in non-functional PTP1B.<ref name="pmid23176256"/> In addition, PTPN1 genetic ablation in [[p53]] deficient mice resulted in an increased incidence of lymphomas and a decrease in overall survival rates.<ref name="pmid16267035"/> In contrast, the PTPN1 gene has been shown to be overexpressed in conjunction with [[HER2]] in [[breast cancer]] cases.<ref name="pmid17347513"/> Murine models of [[HER2]] overexpression in conjunction with PTPN1 knockout resulted in delayed tumor growth and with fewer observed [[metastases]] to the lung suggesting that PTPN1 may have an oncogenic role in [[breast cancer]].<ref name="pmid17347513"/><ref name="pmid17259984"/>

== See also ==
*[[Protein tyrosine phosphatase]]

== References ==
{{reflist | 35em | refs =

<ref name="pmid2164224">{{cite journal | vauthors = Brown-Shimer S, Johnson KA, Lawrence JB, Johnson C, Bruskin A, Green NR, Hill DE | title = Molecular cloning and chromosome mapping of the human gene encoding protein phosphotyrosyl phosphatase 1B | journal = Proc Natl Acad Sci USA | volume = 87 | issue = 13 | pages = 5148–52 |date=Aug 1990 | pmid = 2164224 | pmc = 54279 | doi =10.1073/pnas.87.13.5148 | bibcode = 1990PNAS...87.5148B | doi-access = free }}</ref>

<ref name="Combs2010">{{cite journal | vauthors = Combs AP | title = Recent advances in the discovery of competitive protein tyrosine phosphatase 1B inhibitors for the treatment of diabetes, obesity, and cancer | journal = J. Med. Chem. | volume = 53 | issue = 6 | pages = 2333–44 |date=March 2010 | pmid = 20000419 | doi = 10.1021/jm901090b }}</ref>

<ref name="tonkschar">{{cite journal | vauthors = Tonks NK, Diltz CD, Fischer EH | title = Characterization of the major protein-tyrosine-phosphatases of human placenta | journal = J. Biol. Chem. | volume = 263 | issue = 14 | pages = 6731–7 |date=May 1988 | doi = 10.1016/S0021-9258(18)68703-4 | pmid = 2834387 | url = http://www.jbc.org/content/263/14/6731.full.pdf | doi-access = free }}</ref>

<ref name="tonkspur">{{cite journal | vauthors = Tonks NK, Diltz CD, Fischer EH | title = Purification of the major protein-tyrosine-phosphatases of human placenta | journal = J. Biol. Chem. | volume = 263 | issue = 14 | pages = 6722–30 |date=May 1988 | doi = 10.1016/S0021-9258(18)68702-2 | pmid = 2834386 | url = http://www.jbc.org/content/263/14/6722.full.pdf | doi-access = free }}</ref>

<ref name="Frangioni_1992">{{cite journal | vauthors = Frangioni JV, Beahm PH, Shifrin V, Jost CA, Neel BG | title = The nontransmembrane tyrosine phosphatase PTP-1B localizes to the endoplasmic reticulum via its 35 amino acid C-terminal sequence | journal = Cell | volume = 68 | issue = 3 | pages = 545–60 |date=February 1992 | pmid = 1739967 | doi = 10.1016/0092-8674(92)90190-N | s2cid = 43430621 }}</ref>

<ref name="Chernoff_1990">{{cite journal | vauthors = Chernoff J, Schievella AR, Jost CA, Erikson RL, Neel BG | title = Cloning of a cDNA for a major human protein-tyrosine-phosphatase | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 87 | issue = 7 | pages = 2735–9 |date=April 1990 | pmid = 2157211 | pmc = 53765 | doi = 10.1073/pnas.87.7.2735| bibcode = 1990PNAS...87.2735C | doi-access = free }}</ref>

<ref name="Cicirelli_1990">{{cite journal | vauthors = Cicirelli MF, Tonks NK, Diltz CD, Weiel JE, Fischer EH, Krebs EG | title = Microinjection of a protein-tyrosine-phosphatase inhibits insulin action in Xenopus oocytes | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 87 | issue = 14 | pages = 5514–8 |date=July 1990 | pmid = 2164686 | pmc = 54355 | doi = 10.1073/pnas.87.14.5514 | bibcode = 1990PNAS...87.5514C | doi-access = free }}</ref>

<ref name="Seely_1996">{{cite journal | vauthors = Seely BL, Staubs PA, Reichart DR, Berhanu P, Milarski KL, Saltiel AR, Kusari J, Olefsky JM | title = Protein tyrosine phosphatase 1B interacts with the activated insulin receptor | journal = Diabetes | volume = 45 | issue = 10 | pages = 1379–85 |date=October 1996 | pmid = 8826975 | doi = 10.2337/diabetes.45.10.1379 }}</ref>

<ref name="Elchebly_1999">{{cite journal | vauthors = Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, Ramachandran C, Gresser MJ, Tremblay ML, Kennedy BP | title = Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene | journal = Science | volume = 283 | issue = 5407 | pages = 1544–8 |date=March 1999 | pmid = 10066179 | doi = 10.1126/science.283.5407.1544 | bibcode = 1999Sci...283.1544E }}</ref>

<ref name="Klaman_2000">{{cite journal | vauthors = Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, Zabolotny JM, Moghal N, Lubkin M, Kim YB, Sharpe AH, Stricker-Krongrad A, Shulman GI, Neel BG, Kahn BB | title = Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice | journal = Mol. Cell. Biol. | volume = 20 | issue = 15 | pages = 5479–89 |date=August 2000 | pmid = 10891488 | pmc = 85999 | doi = 10.1128/MCB.20.15.5479-5489.2000 }}</ref>

<ref name="Flint_1997">{{cite journal | vauthors = Flint AJ, Tiganis T, Barford D, Tonks NK | title = Development of "substrate-trapping" mutants to identify physiological substrates of protein tyrosine phosphatases | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 94 | issue = 5 | pages = 1680–5 |date=March 1997 | pmid = 9050838 | pmc = 19976 | doi = 10.1073/pnas.94.5.1680| bibcode = 1997PNAS...94.1680F | doi-access = free }}</ref>

<ref name="Buckley_2002">{{cite journal | vauthors = Buckley DA, Cheng A, Kiely PA, Tremblay ML, O'Connor R | title = Regulation of Insulin-Like Growth Factor Type I (IGF-I) Receptor Kinase Activity by Protein Tyrosine Phosphatase 1B (PTP-1B) and Enhanced IGF-I-Mediated Suppression of Apoptosis and Motility in PTP-1B-Deficient Fibroblasts | journal = Mol. Cell. Biol. | volume = 22 | issue = 7 | pages = 1998–2010 |date=April 2002 | pmid = 11884589 | pmc = 133665 | doi = 10.1128/MCB.22.7.1998-2010.2002 }}</ref>

<ref name="Heinonen_2006">{{cite journal | vauthors = Heinonen KM, Dubé N, Bourdeau A, Lapp WS, Tremblay ML | title = Protein tyrosine phosphatase 1B negatively regulates macrophage development through CSF-1 signaling | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 8 | pages = 2776–81 |date=February 2006 | pmid = 16477024 | pmc = 1413784 | doi = 10.1073/pnas.0508563103 | bibcode = 2006PNAS..103.2776H | doi-access = free }}</ref>

<ref name="Zhu_2007">{{cite journal | vauthors = Zhu S, Bjorge JD, Fujita DJ | title = PTP1B contributes to the oncogenic properties of colon cancer cells through Src activation | journal = Cancer Res. | volume = 67 | issue = 21 | pages = 10129–37 |date=November 2007 | pmid = 17974954 | doi = 10.1158/0008-5472.CAN-06-4338 | doi-access = }}</ref>

<ref name="Myers_2001">{{cite journal | vauthors = Myers MP, Andersen JN, Cheng A, Tremblay ML, Horvath CM, Parisien JP, Salmeen A, Barford D, Tonks NK | title = TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B | journal = J. Biol. Chem. | volume = 276 | issue = 51 | pages = 47771–4 |date=December 2001 | pmid = 11694501 | doi = 10.1074/jbc.C100583200 | doi-access = free }}</ref>

<ref name="Zhang_2006">{{cite journal | vauthors = Zhang Z, Lin SY, Neel BG, Haimovich B | title = Phosphorylated alpha-actinin and protein-tyrosine phosphatase 1B coregulate the disassembly of the focal adhesion kinase x Src complex and promote cell migration | journal = J. Biol. Chem. | volume = 281 | issue = 3 | pages = 1746–54 |date=January 2006 | pmid = 16291744 | doi = 10.1074/jbc.M509590200 | doi-access = free }}</ref>

<ref name="Liu_1996">{{cite journal | vauthors = Liu F, Hill DE, Chernoff J | title = Direct binding of the proline-rich region of protein tyrosine phosphatase 1B to the Src homology 3 domain of p130(Cas) | journal = J. Biol. Chem. | volume = 271 | issue = 49 | pages = 31290–5 |date=December 1996 | pmid = 8940134 | doi = 10.1074/jbc.271.49.31290 | doi-access = free }}</ref>

<ref name="Balsamo_1998">{{cite journal | vauthors = Balsamo J, Arregui C, Leung T, Lilien J | title = The Nonreceptor Protein Tyrosine Phosphatase PTP1B Binds to the Cytoplasmic Domain of N-Cadherin and Regulates the Cadherin–Actin Linkage | journal = J. Cell Biol. | volume = 143 | issue = 2 | pages = 523–32 |date=October 1998 | pmid = 9786960 | pmc = 2132848 | doi = 10.1083/jcb.143.2.523 }}</ref>

<ref name="Stuible_2008">{{cite journal | vauthors = Stuible M, Dubé N, Tremblay ML | title = PTP1B regulates cortactin tyrosine phosphorylation by targeting Tyr446 | journal = J. Biol. Chem. | volume = 283 | issue = 23 | pages = 15740–6 |date=June 2008 | pmid = 18387954 | doi = 10.1074/jbc.M710534200 | pmc = 3259645 | doi-access = free }}</ref>

<ref name="Dubé_2004">{{cite journal | vauthors = Dubé N, Cheng A, Tremblay ML | title = The role of protein tyrosine phosphatase 1B in Ras signaling | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 7 | pages = 1834–9 |date=February 2004 | pmid = 14766979 | pmc = 357013 | doi = 10.1073/pnas.0304242101 | bibcode = 2004PNAS..101.1834D | doi-access = free }}</ref>

<ref name="pmid10889023">{{cite journal | vauthors = Sarmiento M, Puius YA, Vetter SW, Keng YF, Wu L, Zhao Y, Lawrence DS, Almo SC, Zhang ZY | title = Structural basis of plasticity in protein tyrosine phosphatase 1B substrate recognition | journal = Biochemistry | volume = 39 | issue = 28 | pages = 8171–9 |date=July 2000 | pmid = 10889023 | doi = 10.1021/bi000319w }}</ref>

<ref name="pmid8621392">{{cite journal | vauthors = Zhang ZY, Walsh AB, Wu L, McNamara DJ, Dobrusin EM, Miller WT | title = Determinants of substrate recognition in the protein-tyrosine phosphatase, PTP1 | journal = J. Biol. Chem. | volume = 271 | issue = 10 | pages = 5386–92 |date=March 1996 | pmid = 8621392 | doi = 10.1074/jbc.271.10.5386 | doi-access = free }}</ref>

<ref name="pmid10660596">{{cite journal | vauthors = Goldstein BJ, Bittner-Kowalczyk A, White MF, Harbeck M | title = Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein | journal = J. Biol. Chem. | volume = 275 | issue = 6 | pages = 4283–9 |date=February 2000 | pmid = 10660596 | doi = 10.1074/jbc.275.6.4283 | doi-access = free }}</ref>

<ref name="pmid11579209">{{cite journal | vauthors = Ravichandran LV, Chen H, Li Y, Quon MJ | title = Phosphorylation of PTP1B at Ser(50) by Akt impairs its ability to dephosphorylate the insulin receptor | journal = Mol. Endocrinol. | volume = 15 | issue = 10 | pages = 1768–80 |date=October 2001 | pmid = 11579209 | doi = 10.1210/mend.15.10.0711 | doi-access = free }}</ref>

<ref name="Tonks_2003">{{cite journal | vauthors = Tonks NK | title = PTP1B: from the sidelines to the front lines! | journal = FEBS Letters | volume = 546 | issue = 1 | pages = 140–8 | date = Jul 3, 2003 | pmid = 12829250 | doi=10.1016/s0014-5793(03)00603-3| s2cid = 21205538 | doi-access = free }}</ref>

<ref name="pmid8128219">{{cite journal | vauthors = Barford D, Flint AJ, Tonks NK | title = Crystal structure of human protein tyrosine phosphatase 1B | journal = Science | volume = 263 | issue = 5152 | pages = 1397–404 | date = March 1994 | pmid = 8128219 | doi = 10.1126/science.8128219| bibcode = 1994Sci...263.1397B }}</ref>

<ref name="sundaresan_1995">{{cite journal | vauthors = Sundaresan M, Yu ZX, Ferrans VJ, Irani K, Finkel T | title = Requirement for generation of H2O2 for platelet-derived growth factor signal transduction | journal = Science | volume = 270 | issue = 5234 | pages = 296–9 | date = October 1995 | pmid = 7569979 | doi = 10.1126/science.270.5234.296| bibcode = 1995Sci...270..296S | s2cid = 8065388 | url = https://zenodo.org/record/1231056 }}</ref>

<ref name="pmid9624118">{{cite journal | vauthors = Lee SR, Kwon KS, Kim SR, Rhee SG | title = Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor | journal = J. Biol. Chem. | volume = 273 | issue = 25 | pages = 15366–72 | date = June 1998 | pmid = 9624118 | doi = 10.1074/jbc.273.25.15366| doi-access = free}}</ref>

<ref name="pmid11297536">{{cite journal | vauthors = Mahadev K, Zilbering A, Zhu L, Goldstein BJ | title = Insulin-stimulated hydrogen peroxide reversibly inhibits protein-tyrosine phosphatase 1b in vivo and enhances the early insulin action cascade | journal = J. Biol. Chem. | volume = 276 | issue = 24 | pages = 21938–42 | year = 2001 | pmid = 11297536 | doi = 10.1074/jbc.C100109200 | doi-access = free }}</ref>

<ref name="pmid19782770">{{cite journal | vauthors = Lessard L, Stuible M, Tremblay ML | title = The two faces of PTP1B in cancer | journal = Biochim. Biophys. Acta | volume = 1804 | issue = 3 | pages = 613–9 | year = 2010 | pmid = 19782770 | doi = 10.1016/j.bbapap.2009.09.018 }}</ref>

<ref name="pmid23176256">{{cite journal | vauthors = Tonks NK | title = Protein tyrosine phosphatases — from housekeeping enzymes to master regulators of signal transduction | journal = FEBS J. | volume = 280 | issue = 2 | pages = 346–78 | year = 2013 | pmid = 23176256 | pmc = 3662559 | doi = 10.1111/febs.12077 }}</ref>

<ref name="pmid20814956">{{cite journal | vauthors = Thareja S, Aggarwal S, Bhardwaj TR, Kumar M | title = Protein tyrosine phosphatase 1B inhibitors: a molecular level legitimate approach for the management of diabetes mellitus | journal = Med Res Rev | volume = 32 | issue = 3 | pages = 459–517 | year = 2012 | pmid = 20814956 | doi = 10.1002/med.20219 | s2cid = 23121386 }}</ref>

<ref name="pmid17259984">{{cite journal | vauthors = Julien SG, Dubé N, Read M, Penney J, Paquet M, Han Y, Kennedy BP, Muller WJ, Tremblay ML | title = Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis | journal = Nat. Genet. | volume = 39 | issue = 3 | pages = 338–46 | year = 2007 | pmid = 17259984 | doi = 10.1038/ng1963 | s2cid = 33612091 }}</ref>

<ref name="pmid17347513">{{cite journal | vauthors = Bentires-Alj M, Neel BG | title = Protein-tyrosine phosphatase 1B is required for HER2/Neu-induced breast cancer | journal = Cancer Res. | volume = 67 | issue = 6 | pages = 2420–4 | year = 2007 | pmid = 17347513 | doi = 10.1158/0008-5472.CAN-06-4610 | doi-access = free }}</ref>

<ref name="pmid16267035">{{cite journal | vauthors = Dubé N, Bourdeau A, Heinonen KM, Cheng A, Loy AL, Tremblay ML | title = Genetic ablation of protein tyrosine phosphatase 1B accelerates lymphomagenesis of p53-null mice through the regulation of B-cell development | journal = Cancer Res. | volume = 65 | issue = 21 | pages = 10088–95 | year = 2005 | pmid = 16267035 | doi = 10.1158/0008-5472.CAN-05-1353 | doi-access = free }}</ref>

<ref name="pmid15186772">{{cite journal | vauthors = Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T | title = Protein tyrosine phosphatases in the human genome | journal = Cell | volume = 117 | issue = 6 | pages = 699–711 | year = 2004 | pmid = 15186772 | doi = 10.1016/j.cell.2004.05.018 | s2cid = 18072568 | doi-access = free }}</ref>

<ref name="pmid12802338 ">{{cite journal | vauthors = Salmeen A, Andersen JN, Myers MP, Meng TC, Hinks JA, Tonks NK, Barford D | title = Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate | journal = Nature | volume = 423 | issue = 6941 | pages = 769–73 | year = 2003 | pmid = 12802338 | doi = 10.1038/nature01680 | bibcode = 2003Natur.423..769S | s2cid = 4416512 }}</ref>

<ref name="pmid12802339">{{cite journal | vauthors = van Montfort RL, Congreve M, Tisi D, Carr R, Jhoti H | title = Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B | journal = Nature | volume = 423 | issue = 6941 | pages = 773–7 | year = 2003 | pmid = 12802339 | doi = 10.1038/nature01681 | bibcode = 2003Natur.423..773V | s2cid = 4424814 }}</ref>


}}

{{PDB Gallery|geneid=5770}}
{{Protein tyrosine phosphatases}}

BRAF

2024-04-23T19:58:42Z

167.201.243.136: Italicized gene abbreviation

{{wiktionary|braf}}
'''BRAF''' may refer to:

* [[Baton Rouge Area Foundation]]
* [[BRAF (gene)|''BRAF'' (gene)]]

{{disambiguation}}

Chymosin

2024-04-23T17:48:52Z

167.201.243.136: Updated wikilink

{{cs1 config|name-list-style=vanc}}
{{Short description|Class of enzymes}}
{{distinguish|text=[[renin]], an enzyme which takes part in regulation of arterial blood pressure}}
{{infobox enzyme
| Name = Chymosin
| EC_number = 3.4.23.4
| CAS_number = 9001-98-3
| GO_code = 0030602
| image = CHYMOSIN COMPLEX WITH THE INHIBITOR CP-113972.jpg
| width =
| caption = Crystal structure of bovine chymosin complex with the inhibitor CP-113972.<ref name="pmid9862200">{{PDB|1CZI}}; {{cite journal | vauthors = Groves MR, Dhanaraj V, Badasso M, Nugent P, Pitts JE, Hoover DJ, Blundell TL | title = A 2.3 A resolution structure of chymosin complexed with a reduced bond inhibitor shows that the active site beta-hairpin flap is rearranged when compared with the native crystal structure | journal = Protein Engineering | volume = 11 | issue = 10 | pages = 833–40 | date = October 1998 | pmid = 9862200 | doi = 10.1093/protein/11.10.833 | url = https://academic.oup.com/peds/article-pdf/11/10/833/18542197/110833.pdf | doi-access = free }}</ref>
}}
'''Chymosin''' {{IPAc-en|ˈ|k|aɪ|m|ə|s|ᵻ|n}} or '''rennin''' {{IPAc-en|ˈ|r|ɛ|n|ᵻ|n}} is a [[protease]] found in [[rennet]]. It is an [[Aspartic protease|aspartic endopeptidase]] belonging to MEROPS A1 family. It is produced by newborn [[ruminant]] animals in the lining of the [[abomasum]] to curdle the milk they ingest, allowing a longer residence in the bowels and better absorption. It is widely used in the production of [[cheese]].

Historically, chymosin was obtained by extracting it from the stomachs of slaughtered calves. Today, most commercial chymosin used in cheese production is produced [[Recombinant DNA|recombinantly]] in {{nobr|''[[Escherichia coli]]''}}, [[Aspergillus awamori|''Aspergillus niger'' var. ''awamori'']], and {{nobr|''[[Kluyveromyces lactis]]''}}.{{citation needed|date=April 2024}}

==Occurrence==
Chymosin is found in a wide range of [[tetrapods]],<ref name=lineage/> although it is best known to be produced by [[ruminant]] animals in the lining of the [[abomasum]]. Chymosin is produced by [[gastric chief cell]]s in newborn mammals<ref name="pmid11534329">{{cite journal | vauthors = Kitamura N, Tanimoto A, Hondo E, Andrén A, Cottrell DF, Sasaki M, Yamada J | title = Immunohistochemical study of the ontogeny of prochymosin--and pepsinogen-producing cells in the abomasum of sheep | journal = Anatomia, Histologia, Embryologia | volume = 30 | issue = 4 | pages = 231–5 | date = August 2001 | pmid = 11534329 | doi = 10.1046/j.1439-0264.2001.00326.x | s2cid = 7552821 }}</ref> to curdle the milk they ingest, allowing a longer residence in the bowels and better absorption. Non-ruminant species that produce chymosin include pigs, cats, seals,<ref name= OMIM>Staff, Online Mendelian Inheritance in Man (OMIM) Database. Last updated February 21, 1997 [http://www.omim.org/entry/118943 Chymosin pseudogene; CYMP prochymosin, included, in the OMIM]</ref> and [[chicken|chick]]s.<ref name=lineage/>

One study reported finding a chymosin-like enzyme in some human infants,<ref>{{cite journal | vauthors = Henschel MJ, Newport MJ, Parmar V | title = Gastric proteases in the human infant | journal = Biology of the Neonate | volume = 52 | issue = 5 | pages = 268–72 | year = 1987 | pmid = 3118972 | doi = 10.1159/000242719 }}</ref> but others have failed to replicate this finding.<ref>{{cite book | vauthors = Szecsi PB, Harboe M | veditors = Rawlings ND, Salvesen G |year=2013|title=Handbook of Proteolytic Enzymes|chapter=Chapter 5: Chymosin|chapter-url=https://www.researchgate.net/publication/278718218|language=en|volume=1|pages=37–42|doi=10.1016/B978-0-12-382219-2.00005-3}}</ref> Humans have a [[pseudogene]] for chymosin that does not generate a protein, found on [[Chromosome 1 (human)|chromosome 1]].<ref name= OMIM/><ref>{{cite book | vauthors = Fox PF | title = Cheese: Chemistry, Physics and Microbiology | date = 28 February 1999 | publisher = Springer | isbn = 9780834213388 | url = https://books.google.com/books?id=U_mj5DANAeoC&q=chymosin+gene+human&pg=PA62 }}</ref> Humans have other proteins to digest milk, such as [[pepsin]] and [[lipase]].<ref>{{cite book | vauthors = Sanderson IR, Walker WA |title=Development of the gastrointestinal tract |date=1999 |publisher=B.C. Decker |location=Hamilton, Ontario |isbn=978-1-55009-081-9 | url = https://books.google.com/books?id=YhgKZ_dvda0C }}</ref>{{rp|262}}

In addition to the primate lineage leading up to humans, some other mammals have also lost the chymosin gene.<ref name=lineage>{{cite journal | vauthors = Lopes-Marques M, Ruivo R, Fonseca E, Teixeira A, Castro LF | title = Unusual loss of chymosin in mammalian lineages parallels neo-natal immune transfer strategies | journal = Molecular Phylogenetics and Evolution | volume = 116 | pages = 78–86 | date = November 2017 | pmid = 28851538 | doi = 10.1016/j.ympev.2017.08.014 }}</ref>

==Enzymatic reaction==
Chymosin is used to bring about the extensive [[Precipitation (chemistry)|precipitation]] and [[curd]] formation in [[cheese]]-making. The native substrate of chymosin is [[K-casein]] which is specifically [[Bond cleavage|cleaved]] at the [[peptide bond]] between amino acid residues 105 and 106, [[phenylalanine]] and [[methionine]].<ref name="Gilliland">{{cite book | vauthors = Gilliland GL, Oliva MT, Dill J | title = Structure and Function of the Aspartic Proteinases | chapter = Functional Implications of the Three-Dimensional Structure of Bovine Chymosin | series = Advances in Experimental Medicine and Biology | volume = 306 | pages = 23–37 | year = 1991 | pmid = 1812710 | doi = 10.1007/978-1-4684-6012-4_3 | isbn = 978-1-4684-6014-8 }}</ref> The resultant product is [[calcium phosphocaseinate]].{{Citation needed|date=August 2010}} When the specific linkage between the [[hydrophobic]] (para-casein) and [[hydrophilic]] (acidic [[glycopeptide]]) groups of [[casein]] is broken, the hydrophobic groups unite and form a [[Three-dimensional space|3D]] network that traps the aqueous phase of the milk.

Charge interactions between [[histidine]]s on the kappa-casein and [[glutamate]]s and [[aspartate]]s of chymosin initiate enzyme binding to the substrate.<ref name="Gilliland"/> When chymosin is not binding substrate, a beta-hairpin, sometimes referred to as "the flap," can hydrogen bond with the active site, therefore covering it and not allowing further binding of substrate.<ref name="pmid9862200"/>

==Examples==
Listed below are the ruminant ''Cym'' gene and corresponding human pseudogene:
{|
|{{infobox nonhuman protein
|Name=Chymosin [Precursor]
|caption=X-ray analysis of calf chymosin <ref name="Newman">{{PDB|4CMS}}; {{cite journal | vauthors = Newman M, Safro M, Frazao C, Khan G, Zdanov A, Tickle IJ, Blundell TL, Andreeva N | display-authors = 6 | title = X-ray analyses of aspartic proteinases. IV. Structure and refinement at 2.2 A resolution of bovine chymosin | journal = Journal of Molecular Biology | volume = 221 | issue = 4 | pages = 1295–309 | date = October 1991 | pmid = 1942052 | doi = 10.1016/0022-2836(91)90934-X }}</ref>
|image=X-RAY ANALYSES OF ASPARTIC PROTEINASES IV. STRUCTURE AND REFINEMENT AT 2.2 ANGSTROMS RESOLUTION OF BOVINE CHYMOSIN.jpg
|width=
|Organism=Bos taurus
|Symbol=Cym
|AltSymbols=CPC
|EntrezGene=529879
|UniProt=P00794
|PDB=4CMS
|ECnumber=
|Chromosome=
|Arm=
|Band=
|LocusSupplementaryData=
}}
|{{infobox protein
|Name=chymosin pseudogene (human)
|caption=
|image=
|width=
|HGNCid=2588
|Symbol=CYMP
|AltSymbols=
|EntrezGene=643160
|OMIM=118943
|RefSeq= NR_003599
|UniProt=
|PDB=
|ECnumber=
|Chromosome=1
|Arm= p
|Band= 13.3
|LocusSupplementaryData=
}}
|}

==Recombinant chymosin==
Because of the imperfections and scarcity of microbial and animal rennets, producers sought replacements. With the development of genetic engineering, it became possible to extract rennet-producing genes from animal stomach and insert them into certain [[bacteria]], [[fungi]] or [[yeasts]] to make them produce chymosin during fermentation.<ref name="pmid6304731">{{cite journal | vauthors = Emtage JS, Angal S, Doel MT, Harris TJ, Jenkins B, Lilley G, Lowe PA | title = Synthesis of calf prochymosin (prorennin) in Escherichia coli | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 80 | issue = 12 | pages = 3671–5 | date = June 1983 | pmid = 6304731 | pmc = 394112 | doi = 10.1073/pnas.80.12.3671 | bibcode = 1983PNAS...80.3671E | doi-access = free }}</ref><ref name="pmid6283469">{{cite journal | vauthors = Harris TJ, Lowe PA, Lyons A, Thomas PG, Eaton MA, Millican TA, Patel TP, Bose CC, Carey NH, Doel MT | display-authors = 6 | title = Molecular cloning and nucleotide sequence of cDNA coding for calf preprochymosin | journal = Nucleic Acids Research | volume = 10 | issue = 7 | pages = 2177–87 | date = April 1982 | pmid = 6283469 | pmc = 320601 | doi = 10.1093/nar/10.7.2177 }}</ref> The genetically modified microorganism is killed after fermentation and chymosin is isolated from the fermentation broth, so that the fermentation-produced chymosin (FPC) used by cheese producers does not contain any GM component or ingredient.<ref name="GMO Database"/> FPC contains the identical chymosin as the animal source, but produced in a more efficient way. FPC products have been on the market since 1990 and are considered the ideal milk-clotting enzyme.<ref name="Law 2010 100–101">{{cite book|author = Law BA | title = Technology of Cheesemaking|year=2010|publisher= Wiley-Blackwell | location = UK | isbn = 978-1-4051-8298-0 | pages = 100–101 |url = http://eu.wiley.com/WileyCDA/WileyTitle/productCd-1405182989.html}}</ref>

FPC was the first artificially produced enzyme to be registered and allowed by the [[US Food and Drug Administration]]. In 1999, about 60% of US [[hard cheese]] was made with FPC<ref name="USDA">{{cite web |url=https://fpc.state.gov/6176.htm|title=Food Biotechnology in the United States: Science, Regulation, and Issues|publisher=U.S. Department of State|access-date=2006-08-14}}</ref> and it has up to 80% of the global market share for rennet.<ref name="pmid16537950">{{cite journal | vauthors = Johnson ME, Lucey JA | title = Major technological advances and trends in cheese | journal = Journal of Dairy Science | volume = 89 | issue = 4 | pages = 1174–8 | date = April 2006 | pmid = 16537950 | doi = 10.3168/jds.S0022-0302(06)72186-5 | doi-access = free }}</ref>

By 2008, approximately 80% to 90% of commercially made cheeses in the US and Britain were made using FPC.<ref name="GMO Database">{{cite web|url=http://www.gmo-compass.org/eng/database/enzymes/83.chymosin.html|publisher=GMO Compass|title=Chymosin|access-date=2011-03-03|url-status=dead|archive-url=https://web.archive.org/web/20150326181805/http://www.gmo-compass.org/eng/database/enzymes/83.chymosin.html|archive-date=2015-03-26}}</ref> The most widely used fermentation-produced chymosin is produced either using the fungus ''[[Aspergillus niger]]'' or using ''[[Kluyveromyces lactis]]''.

FPC contains only chymosin B,<ref>Bovine chymosins A and B differ by one amino acid residue. This is probably an alleic variant, according to Uniprot:P00794. The two isoforms have identical catalytic activity, so any improvement in the product is due to the elimination of other impurities.</ref> achieving a higher degree of purity compared with animal rennet. FPC can deliver several benefits to the cheese producer compared with animal or microbial rennet, such as higher production yield, better curd texture and reduced bitterness.<ref name="Law 2010 100–101"/>

== References ==
{{reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Foltmann B | title = A review on prorennin and rennin | journal = Comptes-Rendus des Travaux du Laboratoire Carlsberg | volume = 35 | issue = 8 | pages = 143–231 | year = 1966 | pmid = 5330666 }}
* {{cite journal | vauthors = Visser S, Slangen CJ, van Rooijen PJ | title = Peptide substrates for chymosin (rennin). Interaction sites in kappa-casein-related sequences located outside the (103-108)-hexapeptide region that fits into the enzyme's active-site cleft | journal = The Biochemical Journal | volume = 244 | issue = 3 | pages = 553–8 | date = June 1987 | pmid = 3128264 | pmc = 1148031 | doi = 10.1042/bj2440553 }}
{{refend}}

== External links ==
* The [[MEROPS]] online database for peptidases and their inhibitors: [https://www.ebi.ac.uk/merops/cgi-bin/pepsum?id=A01.006 A01.006]

{{Aspartic acid proteases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

[[Category:EC 3.4.23]]

Library (biology)

2024-04-22T21:21:13Z

167.201.243.136: /* Overview of cDNA library preparation techniques */ Added citations needed template

{{Short description|Collection of genetic material fragments}}
{{More citations needed|date=December 2009}}
[[File:Site saturation mutagenesis.svg|thumb|[[Site saturation mutagenesis]] is a type of [[site-directed mutagenesis]]. This image shows the saturation mutagenesis of a single position in a theoretical 10-residue protein. The wild type version of the protein is shown at the top, with M representing the first amino acid methionine, and * representing the termination of translation. All 19 mutants of the isoleucine at position 5 are shown below.]]

[[File:How random DNA libraries sample sequence space.pdf|thumb|How DNA libraries generated by [[Mutagenesis (molecular biology technique)#Random mutagenesis|random mutagenesis]] sample sequence space. The amino acid substituted into a given position is shown. Each dot or set of connected dots is one member of the library. Error-prone PCR randomly mutates some residues to other amino acids. Alanine scanning replaces each residue of the protein with alanine, one-by-one. Site saturation substitutes each of the 20 possible amino acids (or some subset of them) at a single position, one-by-one.]]

In [[molecular biology]], a '''library''' is a collection of [[genetic material]] fragments that are stored and propagated in a population of microbes through the process of [[molecular cloning]]. There are different types of DNA libraries, including [[CDNA library|cDNA libraries]] (formed from [[Complementary DNA|reverse-transcribed RNA]]), [[Genomic library|genomic libraries]] (formed from genomic DNA) and randomized mutant libraries (formed by de novo gene synthesis where alternative nucleotides or codons are incorporated). DNA library technology is a mainstay of current [[molecular biology]], [[genetic engineering]], and [[protein engineering]], and the applications of these libraries depend on the source of the original DNA fragments. There are differences in the [[cloning vectors]] and techniques used in library preparation, but in general each DNA fragment is uniquely inserted into a cloning vector and the pool of recombinant DNA molecules is then transferred into a population of [[bacteria]] (a [[Bacterial Artificial Chromosome]] or BAC library) or yeast such that each organism contains on average one construct (vector + insert). As the population of organisms is grown in culture, the DNA molecules contained within them are copied and propagated (thus, "cloned").

==Terminology==
The term "library" can refer to a population of organisms, each of which carries a DNA molecule inserted into a cloning vector, or alternatively to the collection of all of the cloned vector molecules.

===cDNA libraries===
{{Main|cDNA library}}

A [[cDNA library]] represents a sample of the [[mRNA]] purified from a particular source (either a collection of cells, a particular tissue, or an entire organism), which has been converted back to a DNA template by the use of the enzyme [[reverse transcriptase]]. It thus represents the genes that were being actively transcribed in that particular source under the physiological, developmental, or environmental conditions that existed when the mRNA was purified. cDNA libraries can be generated using techniques that promote "full-length" clones or under conditions that generate shorter fragments used for the identification of "[[expressed sequence tag]]s".

cDNA libraries are useful in reverse genetics, but they only represent a very small (less than 1%) portion of the overall genome in a given organism.

Applications of cDNA libraries include:
* Discovery of novel genes
* Cloning of full-length cDNA molecules for ''in vitro'' study of gene function
* Study of the repertoire of mRNAs expressed in different cells or tissues
* Study of [[alternative splicing]] in different cells or tissues

===Genomic libraries===
{{Main|genomic library}}

A [[genomic library]] is a set of clones that together represents the entire genome of a given organism. The number of clones that constitute a genomic library depends on (1) the size of the genome in question and (2) the insert size tolerated by the particular [[cloning vector]] system. For most practical purposes, the tissue source of the genomic DNA is unimportant because each cell of the body contains virtually identical DNA (with some exceptions).

Applications of genomic libraries include:
* Determining the complete genome sequence of a given organism (see [[genome project]])
* Serving as a source of genomic sequence for generation of [[transgenic animal]]s through [[genetic engineering]]
* Study of the function of [[regulatory sequences]] ''in vitro''
* Study of [[genetic mutation]]s in [[cancer]] tissues

===Synthetic mutant libraries===
[[File:Site-directed mutagenesis library cloning steps.pdf|thumb|Depiction of one common way to clone a site-directed mutagenesis library (i.e., using degenerate oligos). The gene of interest is PCRed with oligos that contain a region that is perfectly complementary to the template (blue), and one that differs from the template by one or more nucleotides (red). Many such primers containing degeneracy in the non-complementary region are pooled into the same PCR, resulting in many different PCR products with different mutations in that region (individual mutants shown with different colors below).]]

In contrast to the library types described above, a variety of artificial methods exist for making libraries of variant genes.<ref name=":0">{{Cite journal|last1=Wajapeyee|first1=Narendra|last2=Liu|first2=Alex Y.|last3=Forloni|first3=Matteo|date=2018-03-01|title=Random Mutagenesis Using Error-Prone DNA Polymerases|journal=Cold Spring Harbor Protocols|language=en|volume=2018|issue=3|pages=pdb.prot097741|doi=10.1101/pdb.prot097741|issn=1940-3402|pmid=29496818}}</ref> Variation throughout the gene can be introduced randomly by either [[error-prone PCR]],<ref>{{Citation|last1=McCullum|first1=Elizabeth O.|title=Random Mutagenesis by Error-Prone PCR|volume=634|date=2010|work=In Vitro Mutagenesis Protocols: Third Edition|pages=103–109|editor-last=Braman|editor-first=Jeff|series=Methods in Molecular Biology|publisher=Humana Press|language=en|doi=10.1007/978-1-60761-652-8_7|pmid=20676978|isbn=9781607616528|last2=Williams|first2=Berea A. R.|last3=Zhang|first3=Jinglei|last4=Chaput|first4=John C.}}</ref> [[DNA shuffling]] to recombine parts of similar genes together,<ref>{{cite journal|vauthors=Crameri A, Raillard SA, Bermudez E, Stemmer WP|date=January 1998|title=DNA shuffling of a family of genes from diverse species accelerates directed evolution|journal=Nature|volume=391|issue=6664|pages=288–91|doi=10.1038/34663|pmid=9440693|bibcode=1998Natur.391..288C|s2cid=4352696}}</ref> or transposon-based methods to introduce [[indel]]s.<ref>{{cite journal|vauthors=Jones DD|date=May 2005|title=Triplet nucleotide removal at random positions in a target gene: the tolerance of TEM-1 beta-lactamase to an amino acid deletion|journal=Nucleic Acids Research|volume=33|issue=9|pages=e80|doi=10.1093/nar/gni077|pmc=1129029|pmid=15897323}}</ref>
Alternatively, mutations can be targeted to specific codons during [[Artificial gene synthesis|''de novo'' synthesis]] or [[saturation mutagenesis]] to construct one or more [[Point mutation|point mutants]] of a gene in a controlled way.<ref>{{Cite journal|last1=Wang|first1=Tian-Wen|last2=Zhu|first2=Hu|last3=Ma|first3=Xing-Yuan|last4=Zhang|first4=Ting|last5=Ma|first5=Yu-Shu|last6=Wei|first6=Dong-Zhi|date=2006-09-01|title=Mutant library construction in directed molecular evolution|journal=Molecular Biotechnology|language=en|volume=34|issue=1|pages=55–68|doi=10.1385/MB:34:1:55|pmid=16943572|s2cid=44393645|issn=1559-0305}}</ref> This results in a mixture of double stranded DNA molecules which represent variants of the original gene.

The [[Protein expression (biotechnology)|expressed]] proteins from these libraries can then be screened for variants which exhibit favorable properties (e.g. stability, binding affinity or enzyme activity). This can be repeated in cycles of creating gene variants and screening the expression products in a [[directed evolution]] process.<ref name=":0" />

==Overview of cDNA library preparation techniques==
{{citations needed|section|date=April 2024}}
===DNA extraction===
If creating an mRNA library (i.e. with cDNA clones), there are several possible protocols for isolating full length mRNA. To extract DNA for genomic DNA (also known as gDNA) libraries, a DNA mini-prep may be useful.

===Insert preparation===
cDNA libraries require care to ensure that full length clones of mRNA are captured as cDNA (which will later be inserted into vectors). Several protocols have been designed to optimise the synthesis of the 1st cDNA strand and the 2nd cDNA strand for this reason, and also to make directional cloning into the vector more likely.

gDNA fragments are generated from the extracted gDNA by using non-specific frequent cutter restriction enzymes.

===Vectors===
The nucleotide sequences of interest are preserved as inserts to a [[plasmid]] or the genome of a [[bacteriophage]] that has been used to infect bacterial cells.

Vectors are propagated most commonly in bacterial cells, but if using a YAC (Yeast Artificial Chromosome) then yeast cells may be used. Vectors could also be propagated in viruses, but this can be time-consuming and tedious. However, the high transfection efficiency achieved by using viruses (often phages) makes them useful for packaging the vector (with the ligated insert) and then introducing them into the bacterial (or yeast) cell.

Additionally, for cDNA libraries, a system using the Lambda Zap II phage, ExAssist, and 2 E. coli species has been developed. A Cre-Lox system using loxP sites and the in vivo expression of the recombinase enzyme can also be used instead. These are examples of in vivo excision systems. In vitro excision involves subcloning often using traditional restriction enzymes and cloning strategies. In vitro excision can be more time-consuming and may require more "hands-on" work than in vivo excision systems. In either case, the systems allow the movement of the vector from the phage into a live cell, where the vector can replicate and propagate until the library is to be used.

==Using libraries==
[[File:Applying synthetic biology tools to optimize production of chemicals by cells.svg|thumb|Workflow for screening a synthetic library to identify cells producing a chemical of interest.]]

This involves "screening" for the sequences of interest. There are multiple possible methods to achieve this.

==References==
{{reflist|30em}}

== External links ==
{{Library resources box
|onlinebooks=no
|by=no
|lcheading=Gene libraries
|label=Gene libraries}}

{{DEFAULTSORT:Library (Biology)}}
[[Category:Molecular biology]]
[[Category:Genetic engineering]]

TPCN1

2024-04-16T21:23:32Z

167.201.243.136: /* Filoviral Infections */ Section header to sentence case per MOS:HEADINGS

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}

'''Two pore segment channel 1''' ('''TPC1''') is a human [[protein]] encoded by the '''''TPCN1''''' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: two pore segment channel 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=53373}}</ref> The protein encoded by this gene is an [[ion channel]]. In contrast to other [[calcium channel|calcium]] and [[sodium channel]]s which have four homologous domains, each containing six transmembrane segments (S1 to S6), TPCN1 only contains two domains (each containing segments S1 to S6).<ref name="pmid10574461">{{cite journal | vauthors = Hirosawa M, Nagase T, Ishikawa K, Kikuno R, Nomura N, Ohara O | title = Characterization of cDNA clones selected by the GeneMark analysis from size-fractionated cDNA libraries from human brain | journal = DNA Research | volume = 6 | issue = 5 | pages = 329–36 | date = October 1999 | pmid = 10574461 | doi = 10.1093/dnares/6.5.329 | doi-access = free }}</ref><ref name="pmid10753632">{{cite journal | vauthors = Ishibashi K, Suzuki M, Imai M | title = Molecular cloning of a novel form (two-repeat) protein related to voltage-gated sodium and calcium channels | journal = Biochemical and Biophysical Research Communications | volume = 270 | issue = 2 | pages = 370–6 | date = April 2000 | pmid = 10753632 | doi = 10.1006/bbrc.2000.2435 }}</ref><ref name="pmid16382101">{{cite journal | vauthors = Clapham DE, Garbers DL | title = International Union of Pharmacology. L. Nomenclature and structure-function relationships of CatSper and two-pore channels | journal = Pharmacological Reviews | volume = 57 | issue = 4 | pages = 451–4 | date = December 2005 | pmid = 16382101 | doi = 10.1124/pr.57.4.7 | s2cid = 35096827 }}</ref>

==Structure==
The structure of a TPC1 [[ortholog]] from ''[[Arabidopsis thaliana]]'' has been solved by two laboratories.<ref>{{cite journal | vauthors = Guo J, Zeng W, Chen Q, Lee C, Chen L, Yang Y, Cang C, Ren D, Jiang Y | title = Structure of the voltage-gated two-pore channel TPC1 from Arabidopsis thaliana | journal = Nature | volume = 531 | issue = 7593 | pages = 196–201 | date = March 2016 | pmid = 26689363 | doi = 10.1038/nature16446 | pmc=4841471| bibcode = 2016Natur.531..196G }}</ref><ref>{{cite journal | vauthors = Kintzer AF, Stroud RM | title = Structure, inhibition and regulation of two-pore channel TPC1 from Arabidopsis thaliana | journal = Nature | volume = 531 | issue = 7593 | pages = 258–62 | date = March 2016 | pmid = 26961658 | doi = 10.1038/nature17194 | pmc=4863712| bibcode = 2016Natur.531..258K }}</ref> The structures were solved using [[X-ray crystallography]] and contained the fold of a [[voltage-gated ion channel]] and [[EF hand]]s. Only a single voltage sensor domain appears to responsible for voltage sensing.

==Filoviral infections==
Genetic knockout and pharmacological inhibition experiments demonstrate that the [[two-pore channel]]s, [[TPC1]] and [[TPC2]], are required for infection by Filoviruses [[Ebola]] and [[Marburg]] in mice.<ref>{{cite journal | vauthors = Sakurai Y, Kolokoltsov AA, Chen CC, Tidwell MW, Bauta WE, Klugbauer N, Grimm C, Wahl-Schott C, Biel M, Davey RA | title = Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment | journal = Science | volume = 347 | issue = 6225 | pages = 995–8 | date = February 2015 | pmid = 25722412 | doi = 10.1126/science.1258758 | pmc=4550587}}</ref>

== See also ==
* [[Two-pore channel]]

== References ==
{{Reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Ishibashi K, Suzuki M, Imai M | title = Molecular cloning of a novel form (two-repeat) protein related to voltage-gated sodium and calcium channels | journal = Biochemical and Biophysical Research Communications | volume = 270 | issue = 2 | pages = 370–6 | date = April 2000 | pmid = 10753632 | doi = 10.1006/bbrc.2000.2435 }}
* {{cite journal | vauthors = Hirosawa M, Nagase T, Ishikawa K, Kikuno R, Nomura N, Ohara O | title = Characterization of cDNA clones selected by the GeneMark analysis from size-fractionated cDNA libraries from human brain | journal = DNA Research | volume = 6 | issue = 5 | pages = 329–36 | date = October 1999 | pmid = 10574461 | doi = 10.1093/dnares/6.5.329 | doi-access = free }}
* {{cite journal | vauthors = Clapham DE, Garbers DL | title = International Union of Pharmacology. L. Nomenclature and structure-function relationships of CatSper and two-pore channels | journal = Pharmacological Reviews | volume = 57 | issue = 4 | pages = 451–4 | date = December 2005 | pmid = 16382101 | doi = 10.1124/pr.57.4.7 | s2cid = 35096827 }}
* {{cite journal | vauthors = Calcraft PJ, Ruas M, Pan Z, Cheng X, Arredouani A, Hao X, Tang J, Rietdorf K, Teboul L, Chuang KT, Lin P, Xiao R, Wang C, Zhu Y, Lin Y, Wyatt CN, Parrington J, Ma J, Evans AM, Galione A, Zhu MX | title = NAADP mobilizes calcium from acidic organelles through two-pore channels | journal = Nature | volume = 459 | issue = 7246 | pages = 596–600 | date = May 2009 | pmid = 19387438 | pmc = 2761823 | doi = 10.1038/nature08030 | bibcode = 2009Natur.459..596C }}
* {{cite journal | vauthors = Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T | title = Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones | journal = DNA Research | volume = 9 | issue = 3 | pages = 99–106 | date = June 2002 | pmid = 12168954 | doi = 10.1093/dnares/9.3.99 | citeseerx = 10.1.1.500.923 }}
{{refend}}

== External links ==
* {{MeshName|TPCN1+protein,+human}}

{{Ion channels|g1}}

[[Category:Ion channels]]

TPCN2

2024-04-16T21:23:07Z

167.201.243.136: Copy editing

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{cs1 config|name-list-style=vanc}}
{{Infobox_gene}}

'''Two pore segment channel 2''' ('''TPC2''') is a [[protein]] which in humans is encoded by the '''''TPCN2''''' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: two pore segment channel 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=219931}}</ref> TPC2 is an [[ion channel]], however, in contrast to other [[calcium channel|calcium]] and [[sodium channel]]s which have four homologous domains, each containing 6 transmembrane segments (S1 to S6), TPCN1 only contains two domain (each containing segments S1 to S6).<ref name="pmid16382101">{{cite journal | vauthors = Clapham DE, Garbers DL | title = International Union of Pharmacology. L. Nomenclature and structure-function relationships of CatSper and two-pore channels | journal = Pharmacological Reviews | volume = 57 | issue = 4 | pages = 451–4 | date = December 2005 | pmid = 16382101 | doi = 10.1124/pr.57.4.7 | s2cid = 35096827 }}</ref>

==Structure==
TPC2 is homologous to TPC1, the best characterized member of the TPC family. The structure of a TPC1 [[ortholog]] from ''[[Arabidopsis thaliana]]'' has been solved by two laboratories.<ref>{{cite journal | vauthors = Guo J, Zeng W, Chen Q, Lee C, Chen L, Yang Y, Cang C, Ren D, Jiang Y | title = Structure of the voltage-gated two-pore channel TPC1 from Arabidopsis thaliana | journal = Nature | volume = 531 | issue = 7593 | pages = 196–201 | date = March 2016 | pmid = 26689363 | doi = 10.1038/nature16446 | pmc=4841471| bibcode = 2016Natur.531..196G }}</ref><ref>{{cite journal | vauthors = Kintzer AF, Stroud RM | title = Structure, inhibition and regulation of two-pore channel TPC1 from Arabidopsis thaliana | journal = Nature | volume = 531 | issue = 7593 | pages = 258–62 | date = March 2016 | pmid = 26961658 | doi = 10.1038/nature17194 | pmc=4863712| bibcode = 2016Natur.531..258K }}</ref> The structures were solved using [[X-ray crystallography]] and contained the fold of a [[voltage-gated ion channel]] and [[EF hand]]s.

==Filoviral infections==
Genetic knockout and pharmacological inhibition experiments demonstrate that the [[two-pore channel]]s, [[TPC1]] and [[TPC2]], are required for infection by Filoviruses [[Ebola]] and [[Marburg]] in mice.<ref>{{cite journal | vauthors = Sakurai Y, Kolokoltsov AA, Chen CC, Tidwell MW, Bauta WE, Klugbauer N, Grimm C, Wahl-Schott C, Biel M, Davey RA | title = Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment | journal = Science | volume = 347 | issue = 6225 | pages = 995–8 | date = February 2015 | pmid = 25722412 | doi = 10.1126/science.1258758 | pmc=4550587}}</ref>

== See also ==
* [[Two-pore channel]]
{{clear}}

== References ==
{{Reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T, Jakobsdottir M, Steinberg S, Gudjonsson SA, Palsson A, Thorleifsson G, Pálsson S, Sigurgeirsson B, Thorisdottir K, Ragnarsson R, Benediktsdottir KR, Aben KK, Vermeulen SH, Goldstein AM, Tucker MA, Kiemeney LA, Olafsson JH, Gulcher J, Kong A, Thorsteinsdottir U, Stefansson K | title = Two newly identified genetic determinants of pigmentation in Europeans | journal = Nature Genetics | volume = 40 | issue = 7 | pages = 835–7 | date = July 2008 | pmid = 18488028 | doi = 10.1038/ng.160 | s2cid = 13411482 }}
* {{cite journal | vauthors = Suzuki Y, Yamashita R, Shirota M, Sakakibara Y, Chiba J, Mizushima-Sugano J, Nakai K, Sugano S | title = Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions | journal = Genome Research | volume = 14 | issue = 9 | pages = 1711–8 | date = September 2004 | pmid = 15342556 | pmc = 515316 | doi = 10.1101/gr.2435604 }}
* {{cite journal | vauthors = Calcraft PJ, Ruas M, Pan Z, Cheng X, Arredouani A, Hao X, Tang J, Rietdorf K, Teboul L, Chuang KT, Lin P, Xiao R, Wang C, Zhu Y, Lin Y, Wyatt CN, Parrington J, Ma J, Evans AM, Galione A, Zhu MX | title = NAADP mobilizes calcium from acidic organelles through two-pore channels | journal = Nature | volume = 459 | issue = 7246 | pages = 596–600 | date = May 2009 | pmid = 19387438 | pmc = 2761823 | doi = 10.1038/nature08030 | bibcode = 2009Natur.459..596C }}
* {{cite journal | vauthors = Taylor TD, Noguchi H, Totoki Y, Toyoda A, Kuroki Y, Dewar K, Lloyd C, Itoh T, Takeda T, Kim DW, She X, Barlow KF, Bloom T, Bruford E, Chang JL, Cuomo CA, Eichler E, FitzGerald MG, Jaffe DB, LaButti K, Nicol R, Park HS, Seaman C, Sougnez C, Yang X, Zimmer AR, Zody MC, Birren BW, Nusbaum C, Fujiyama A, Hattori M, Rogers J, Lander ES, Sakaki Y | title = Human chromosome 11 DNA sequence and analysis including novel gene identification | journal = Nature | volume = 440 | issue = 7083 | pages = 497–500 | date = March 2006 | pmid = 16554811 | doi = 10.1038/nature04632 | bibcode = 2006Natur.440..497T | doi-access = free }}
* {{cite journal | vauthors = Fu GK, Wang JT, Yang J, Au-Young J, Stuve LL | title = Circular rapid amplification of cDNA ends for high-throughput extension cloning of partial genes | journal = Genomics | volume = 84 | issue = 1 | pages = 205–10 | date = July 2004 | pmid = 15203218 | doi = 10.1016/j.ygeno.2004.01.011 }}
{{refend}}

== External links ==
* {{MeshName|TPCN2+protein,+human}}

{{Ion channels|g1}}

[[Category:Ion channels]]

ZEB1

2024-04-12T22:09:35Z

167.201.243.136: Copy editing per MOS:SPELL09

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Zinc finger E-box-binding homeobox 1''' is a [[protein]] that in humans is encoded by the ''ZEB1'' [[gene]].<ref name="pmid1427828">{{cite journal | vauthors = Williams TM, Montoya G, Wu Y, Eddy RL, Byers MG, Shows TB | title = The TCF8 gene encoding a zinc finger protein (Nil-2-a) resides on human chromosome 10p11.2 | journal = Genomics | volume = 14 | issue = 1 | pages = 194–6 | date = September 1992 | pmid = 1427828 | doi = 10.1016/S0888-7543(05)80307-6 }}</ref><ref name="pmid1840704">{{cite journal | vauthors = Williams TM, Moolten D, Burlein J, Romano J, Bhaerman R, Godillot A, Mellon M, Rauscher FJ, Kant JA | title = Identification of a zinc finger protein that inhibits IL-2 gene expression | journal = Science | volume = 254 | issue = 5039 | pages = 1791–4 | date = December 1991 | pmid = 1840704 | doi = 10.1126/science.1840704 | bibcode = 1991Sci...254.1791W }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: ZEB1 zinc finger E-box binding homeobox 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6935}}</ref>

ZEB1 (previously known as TCF8) encodes a [[zinc finger]] and [[homeodomain]] [[transcription factor]] that represses T-lymphocyte-specific [[interleukin 2|IL2]] gene expression by binding to a negative regulatory domain 100 nucleotides 5-prime of the IL2 [[transcription start site]].<ref name="entrez" /><ref name="pmid1840704"/> ZEB1 and its mammalian paralog [[ZEB2]] belongs to the Zeb family within the ZF (zinc finger) class of homeodomain transcription factors. ZEB1 protein has seven zinc fingers and one homeodomain.<ref name="pmid26464018">{{cite journal | vauthors = Bürglin TR, Affolter M | title = Homeodomain proteins: an update | journal = Chromosoma | volume = 125 | issue = 3 | pages = 497–521 | date = July 2016 | pmid = 26464018 | pmc = 4901127 | doi = 10.1007/s00412-015-0543-8 }}</ref> The structure of the homeodomain is shown on the right.

== Clinical significance ==
Mutations of the gene are linked to [[posterior polymorphous corneal dystrophy 3]]. ZEB1 downregulates [[E-cadherin]] and induces [[epithelial to mesenchymal transition]] in breast and other carcinomas<ref name="pmid15674322">{{cite journal | vauthors = Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M, Berx G, Cano A, Beug H, Foisner R | title = DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells | journal = Oncogene | volume = 24 | issue = 14 | pages = 2375–85 | date = March 2005 | pmid = 15674322 | doi = 10.1038/sj.onc.1208429 | doi-access=free}}</ref> A recent study suggested its contributing role in [[lung cancer]] invasiveness and metastasis development.<ref name="pmid24468793">{{cite journal | vauthors = Liu W, Huang YJ, Liu C, Yang YY, Liu H, Cui JG, Cheng Y, Gao F, Cai JM, Li BL | title = Inhibition of TBK1 attenuates radiation-induced epithelial-mesenchymal transition of A549 human lung cancer cells via activation of GSK-3β and repression of ZEB1 | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 94 | issue = 4 | pages = 362–70 | date = April 2014 | pmid = 24468793 | doi = 10.1038/labinvest.2013.153 | doi-access = free }}</ref> Overexpression of ZEB1 has been identified as a potential risk factor for recurrence and poor prognosis in several types of cancers.<ref name="pmid36076506">{{cite journal | vauthors = Lu J, Fei F, Wu C, Mei J, Xu J, Lu P | title = ZEB1: Catalyst of immune escape during tumor metastasis | journal = Biomed Pharmacother | volume = 153 | issue = | pages = 113490 | date = September 2022 | pmid = 36076506 | doi = 10.1016/j.biopha.2022.113490 | doi-access = free }}</ref>

== References ==
{{Reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Franklin AJ, Jetton TL, Shelton KD, Magnuson MA | title = BZP, a novel serum-responsive zinc finger protein that inhibits gene transcription | journal = Molecular and Cellular Biology | volume = 14 | issue = 10 | pages = 6773–88 | date = October 1994 | pmid = 7935395 | pmc = 359208 | doi = 10.1128/MCB.14.10.6773}}
* {{cite journal | vauthors = Watanabe Y, Kawakami K, Hirayama Y, Nagano K | title = Transcription factors positively and negatively regulating the Na,K-ATPase alpha 1 subunit gene | journal = Journal of Biochemistry | volume = 114 | issue = 6 | pages = 849–55 | date = December 1993 | pmid = 8138542 | doi = 10.1093/oxfordjournals.jbchem.a124267}}
* {{cite journal | vauthors = Ikeda K, Halle JP, Stelzer G, Meisterernst M, Kawakami K | title = Involvement of negative cofactor NC2 in active repression by zinc finger-homeodomain transcription factor AREB6 | journal = Molecular and Cellular Biology | volume = 18 | issue = 1 | pages = 10–8 | date = January 1998 | pmid = 9418848 | pmc = 121442 | doi = 10.1128/mcb.18.1.10 }}
* {{cite journal | vauthors = Turner J, Crossley M | title = Cloning and characterization of mCtBP2, a co-repressor that associates with basic Krüppel-like factor and other mammalian transcriptional regulators | journal = The EMBO Journal | volume = 17 | issue = 17 | pages = 5129–40 | date = September 1998 | pmid = 9724649 | pmc = 1170841 | doi = 10.1093/emboj/17.17.5129 }}
* {{cite journal | vauthors = Postigo AA, Dean DC | title = ZEB represses transcription through interaction with the corepressor CtBP | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 12 | pages = 6683–8 | date = June 1999 | pmid = 10359772 | pmc = 21975 | doi = 10.1073/pnas.96.12.6683 | bibcode = 1999PNAS...96.6683P | doi-access = free }}
* {{cite journal | vauthors = Hlubek F, Löhberg C, Meiler J, Jung A, Kirchner T, Brabletz T | title = Tip60 is a cell-type-specific transcriptional regulator | journal = Journal of Biochemistry | volume = 129 | issue = 4 | pages = 635–41 | date = April 2001 | pmid = 11275565 | doi = 10.1093/oxfordjournals.jbchem.a002901 }}
* {{cite journal | vauthors = Locklin RM, Riggs BL, Hicok KC, Horton HF, Byrne MC, Khosla S | title = Assessment of gene regulation by bone morphogenetic protein 2 in human marrow stromal cells using gene array technology | journal = Journal of Bone and Mineral Research | volume = 16 | issue = 12 | pages = 2192–204 | date = December 2001 | pmid = 11760832 | doi = 10.1359/jbmr.2001.16.12.2192 | s2cid = 25397480 | doi-access = free }}
* {{cite journal | vauthors = Shaheduzzaman S, Krishnan V, Petrovic A, Bittner M, Meltzer P, Trent J, Venkatesan S, Zeichner S | title = Effects of HIV-1 Nef on cellular gene expression profiles | journal = Journal of Biomedical Science | volume = 9 | issue = 1 | pages = 82–96 | year = 2002 | pmid = 11810028 | doi = 10.1007/BF02256581 }}
* {{cite journal | vauthors = Guaita S, Puig I, Franci C, Garrido M, Dominguez D, Batlle E, Sancho E, Dedhar S, De Herreros AG, Baulida J | title = Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression | journal = The Journal of Biological Chemistry | volume = 277 | issue = 42 | pages = 39209–16 | date = October 2002 | pmid = 12161443 | doi = 10.1074/jbc.M206400200 | doi-access = free }}
* {{cite journal | vauthors = Costantino ME, Stearman RP, Smith GE, Darling DS | title = Cell-specific phosphorylation of Zfhep transcription factor | journal = Biochemical and Biophysical Research Communications | volume = 296 | issue = 2 | pages = 368–73 | date = August 2002 | pmid = 12163027 | doi = 10.1016/S0006-291X(02)00880-X | pmc = 3682420 }}
* {{cite journal | vauthors = Postigo AA | title = Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway | journal = The EMBO Journal | volume = 22 | issue = 10 | pages = 2443–52 | date = May 2003 | pmid = 12743038 | pmc = 155983 | doi = 10.1093/emboj/cdg225 }}
* {{cite journal | vauthors = Postigo AA, Depp JL, Taylor JJ, Kroll KL | title = Regulation of Smad signaling through a differential recruitment of coactivators and corepressors by ZEB proteins | journal = The EMBO Journal | volume = 22 | issue = 10 | pages = 2453–62 | date = May 2003 | pmid = 12743039 | pmc = 155984 | doi = 10.1093/emboj/cdg226 }}
* {{cite journal | vauthors = Dillner NB, Sanders MM | title = Transcriptional activation by the zinc-finger homeodomain protein delta EF1 in estrogen signaling cascades | journal = DNA and Cell Biology | volume = 23 | issue = 1 | pages = 25–34 | date = January 2004 | pmid = 14965470 | doi = 10.1089/104454904322745907 }}
* {{cite journal | vauthors = Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP | title = Large-scale characterization of HeLa cell nuclear phosphoproteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 33 | pages = 12130–5 | date = August 2004 | pmid = 15302935 | pmc = 514446 | doi = 10.1073/pnas.0404720101 | bibcode = 2004PNAS..10112130B | doi-access = free }}
* {{cite journal | vauthors = Shimizu S, Krafchak C, Fuse N, Epstein MP, Schteingart MT, Sugar A, Eibschitz-Tsimhoni M, Downs CA, Rozsa F, Trager EH, Reed DM, Boehnke M, Moroi SE, Richards JE | title = A locus for posterior polymorphous corneal dystrophy (PPCD3) maps to chromosome 10 | journal = American Journal of Medical Genetics. Part A | volume = 130A | issue = 4 | pages = 372–7 | date = November 2004 | pmid = 15384081 | pmc = 1249494 | doi = 10.1002/ajmg.a.30267 }}

{{refend}}

== External links ==
* {{FactorBook|ZEB1}}

{{PDB Gallery|geneid=6935}}
{{Transcription factors|g3}}

[[Category:Transcription factors]]

{{Gene-10-stub}}

Acrodermatitis chronica atrophicans

2024-04-11T14:38:19Z

167.201.243.136: Added citation needed flag

{{More citations needed|date=August 2020}}

{{Infobox medical condition (new)
| name = Acrodermatitis chronica atrophicans
| synonyms = '''Herxheimer disease'''<ref name="Bolognia">{{cite book |author =Rapini, Ronald P. |author2 =Bolognia, Jean L. |author3 =Jorizzo, Joseph L. |title=Dermatology: 2-Volume Set |publisher=Mosby |location=St. Louis |year=2007 |isbn=978-1-4160-2999-1 }}</ref>{{rp|1102}} and '''Primary diffuse atrophy'''<ref name="Andrews">{{cite book |author =James, William D. |author2 =Berger, Timothy G. |title=Andrews' Diseases of the Skin: clinical Dermatology |publisher=Saunders Elsevier |year=2006 |isbn=978-0-7216-2921-6 |display-authors=etal}}</ref>{{rp|293}}
| image =
| caption =
| pronounce =
| field =
| symptoms =
| complications =
| onset =
| duration =
| types =
| causes = untreated infection with ''Borrelia afzelii''
| risks =
| diagnosis =
| differential =
| prevention =
| treatment =
| medication =
| prognosis =
| frequency =
| deaths =
}}
'''Acrodermatitis chronica atrophicans''' ('''ACA''') is a [[skin rash]] indicative of the third or late stage of European [[Lyme disease|Lyme borreliosis]].

ACA is a [[dermatology|dermatological]] condition that takes a chronically progressive course and finally leads to a widespread [[atrophy]] of the skin. Involvement of the [[peripheral nervous system]] is often observed, specifically [[polyneuropathy]].

This progressive skin process is due to the effect of continuing active infection with the [[spirochete]] ''[[Borrelia afzelii]]'', which is the predominant pathophysiology.<ref name="BMJ2020">{{Cite journal |last1=Kullberg |first1=Bart Jan |last2=Vrijmoeth |first2=Hedwig D. |last3=van de Schoor |first3=Freek |last4=Hovius |first4=Joppe W. |date=2020-05-26 |title=Lyme borreliosis: diagnosis and management |url=https://pubmed.ncbi.nlm.nih.gov/32457042 |journal=BMJ (Clinical Research Ed.) |volume=369 |pages=m1041 |doi=10.1136/bmj.m1041 |issn=1756-1833 |pmid=32457042|s2cid=218911807 }}</ref> ''B. afzelii'' may not be the exclusive [[etiology|etiologic]] agent of ACA; ''Borrelia garinii'' has also been detected.{{citation needed|date=April 2024}}

==Presentation==
The rash caused by ACA is most evident on the extremities. It begins with an [[inflammation|inflammatory]] stage with bluish red discoloration and cutaneous [[Swelling (medical)|swelling]], and concludes several months or years later with an atrophic phase. [[Sclerosis (medicine)|Sclerotic]] skin plaques may also develop.{{citation needed|date=March 2017}} As ACA progresses the skin begins to [[wrinkle]] ([[atrophy]]).

==Cause==
{{Empty section|date=March 2017}}

==Diagnosis==
Generally a two-step approach is followed. First, a screening test involving IgM and IgG ELISA. If the ELISA screening has a positive or equivocal result, then the second step is to perform a Western Blot as a confirmatory test.

Other methods include microscopy and culture (in modified Kelly's medium) of skin biopsy or blood samples.

==Treatment==
[[Antibiotics]] is recommended in treatment of ACA. [[Doxycycline]] is often used.<ref name="BMJ2020"/><ref name="NICE2018">{{Cite book |last=National Guideline Centre (UK) |url=http://www.ncbi.nlm.nih.gov/books/NBK578169/ |title=Evidence review for management of acrodermatitis chronica atrophicans: Lyme disease: diagnosis and management |date=2018 |publisher=[[National Institute for Health and Care Excellence]] (NICE) |isbn=978-1-4731-2919-1 |series=NICE Evidence Reviews Collection |location=London |pmid=35201695}}</ref> Resolution may take several months.<ref name="BMJ2020"/> Skin damage and [[neuropathy|nerve damage]] may persist after treatment.<ref name="BMJ2020"/>

==History==
The first record of ACA was made in 1883 in [[Breslau]], [[Germany]], where a physician named [[Alfred Buchwald]] first delineated it.{{citation needed|date=March 2017}}[[Herxheimer reaction|Herxheimer]] and Hartmann described it in 1902 as a "tissue paper like" [[cutaneous]] atrophy.

==See also==
* [[Erythema migrans]]
* [[List of cutaneous conditions]]
* [[Lyme disease]]

== References ==
{{Reflist}}

== Bibliography ==
* Stanek G & Strle F (2008) ''Lyme Disease—European Perspective''| Infectious Disease Clinics of North America | Volume 22 | Issue 2 | June 2008, Pages 327-339|[http://www.sciencedirect.com/science/article/pii/S0891552008000020 Abstract]

== External links ==
{{Medical resources
| DiseasesDB = 32940
| ICD10 = {{ICD10|L|90|4|l|80}}
| ICD9 = {{ICD9|701.8}}
| ICDO =
| OMIM =
| MedlinePlus =
| eMedicineSubj = derm
| eMedicineTopic = 4
| MeshID =
}}

{{Cutaneous ketatosis, ulcer, atrophy, necrobiosis, and vasculitis}}
{{Medicine}}

{{DEFAULTSORT:Acrodermatitis Chronica Atrophicans}}
[[Category:Abnormalities of dermal fibrous and elastic tissue]]
[[Category:Lyme disease]]
[[Category:Spirochaetes]]
[[Category:Bacterium-related cutaneous conditions]]

DEAD box

2024-04-03T16:39:58Z

167.201.243.136: /* Biological functions */ Added main article template

{{Short description|Family of proteins}}
{{Infobox protein family
| Symbol = DEAD
| Name = DEAD/DEAH box helicase
| image = PDB_1qva_EBI.jpg
| width =
| caption = Structure of the amino terminal domain of yeast initiation factor 4A. PDB {{PDBe|1qva}}<ref>{{Cite journal
| last1 = Johnson | first1 = E. R.
| last2 = McKay | first2 = D. B.
| title = Crystallographic structure of the amino terminal domain of yeast initiation factor 4A, a representative DEAD-box RNA helicase
| journal = RNA
| volume = 5
| issue = 12
| pages = 1526–1534
| year = 1999
| pmid = 10606264
| pmc = 1369875
| doi=10.1017/S1355838299991410
}}</ref>
| Pfam = PF00270
| Pfam_clan = CL0023
| InterPro = IPR011545
| SMART =
| PROSITE = PDOC00039
| MEROPS =
| SCOP = 1qva
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| CDD = cd00268
| CDD2 = cd00046
}}
'''DEAD box proteins''' are involved in an assortment of metabolic processes that typically involve [[RNA]]s, but in some cases also other [[nucleic acid]]s.<ref name="pmid15028736">{{cite journal |author1=Takashi Kikuma |author2=Masaya Ohtsu |author3=Takahiko Utsugi |author4=Shoko Koga |author5=Kohji Okuhara |author6=Toshihiko Eki |author7=Fumihiro Fujimori |author8=Yasufumi Murakami | title = Dbp9p, a Member of the DEAD Box Protein Family, Exhibits DNA Helicase Activity | journal = J. Biol. Chem. | volume = 279 | issue = 20 | pages = 20692–20698 |date=March 2004 | pmid = 15028736 | doi = 10.1074/jbc.M400231200 |doi-access=free }}</ref> They are highly conserved in nine [[sequence motif|motifs]] and can be found in most [[prokaryote]]s and [[eukaryote]]s, but not all. Many organisms, including humans, contain DEAD-box (SF2) [[helicase]]s, which are involved in RNA [[metabolism]].<ref name="pmid15765144">{{cite journal |author2-link=Maurizio Del Poeta|vauthors=Heung LJ, Del Poeta M | title = Unlocking the DEAD-box: a key to cryptococcal virulence? | journal = J. Clin. Invest. | volume = 115 | issue = 3 | pages = 593–5 |date=March 2005 | pmid = 15765144 | pmc = 1052016 | doi = 10.1172/JCI24508 }}</ref>

== DEAD box family ==

DEAD box proteins were first brought to attention in the late 1980s in a study that looked at a group of [[NTP binding site]]s that were similar in sequence to the eIF4A RNA helicase sequence.<ref name="pmid2546125">{{cite journal |vauthors=Gorbalenya AE, Koonin EV, Donchenko AP, Blinov VM | title = Two related superfamilies of putative helicases involved in replication, recombination, repair and expression of DNA and RNA genomes | journal = Nucleic Acids Res. | volume = 17 | issue = 12 | pages = 4713–30 |date=June 1989 | pmid = 2546125 | pmc = 318027 | doi = 10.1093/nar/17.12.4713}}</ref> The results of this study showed that these proteins (p68, SrmB, MSS116, vasa, PL10, mammalian eIF4A, yeast eIF4A) involved in RNA metabolism had several common elements.<ref name="pmid2563148"/> There were nine common sequences found to be conserved amongst the studied species, which is an important criterion of the DEAD box family.<ref name="pmid2563148">{{Cite journal
| last1 = Linder | first1 = P.
| last2 = Lasko | first2 = P. F.
| last3 = Ashburner | first3 = M.
| last4 = Leroy | first4 = P.
| last5 = Nielsen | first5 = P. J.
| last6 = Nishi | first6 = K.
| last7 = Schnier | first7 = J.
| last8 = Slonimski | first8 = P. P.
| doi = 10.1038/337121a0
| title = Birth of the D-E-A-D box
| journal = Nature
| volume = 337
| issue = 6203
| pages = 121–122
| year = 1989
| pmid = 2563148
|bibcode = 1989Natur.337..121L | s2cid = 13529955
}}</ref>

The nine conserved motif from the N-terminal to the C-terminal are named as follows: Q-motif, motif 1, motif 1a, motif 1b, motif II, motif III, motif IV, motif V, and motif VI, as shown in the figure. Motif II is also known as the [[Walker motifs|Walker B motif]] and contains the amino acid sequence D-E-A-D (asp-glu-ala-asp), which gave this family of proteins the name “DEAD box”.<ref name="pmid2563148" /> Motif 1, motif II, the Q motif, and motif VI are all needed for ATP binding and hydrolysis, while motifs, 1a, 1b, III, IV, and V may be involved in intramolecular rearrangements and RNA interaction.<ref name="pmid12535527">{{cite journal |vauthors=Tanner NK, Cordin O, Banroques J, Doère M, Linder P | title = The Q motif: a newly identified motif in DEAD box helicases may regulate ATP binding and hydrolysis | journal = Mol. Cell | volume = 11 | issue = 1 | pages = 127–38 |date=January 2003 | pmid = 12535527 | doi = 10.1016/S1097-2765(03)00006-6| doi-access = free }}</ref>

== Related families ==
{{missing information|section|comparison of motif structure|small=yes|date=October 2021}}
The DEAH and [[SKIV2L|SKI2]] families have had proteins that have been identified to be related to the DEAD box family.<ref name="pmid16008364">{{cite journal |vauthors=Tanaka N, Schwer B | title = Characterization of the NTPase, RNA-binding, and RNA helicase activities of the DEAH-box splicing factor Prp22 | journal = Biochemistry | volume = 44 | issue = 28 | pages = 9795–803 |date=July 2005 | pmid = 16008364 | doi = 10.1021/bi050407m }}</ref><ref name="pmid12522690">{{cite journal |vauthors=Xu J, Wu H, Zhang C, Cao Y, Wang L, Zeng L, Ye X, Wu Q, Dai J, Xie Y, Mao Y | title = Identification of a novel human DDX40gene, a new member of the DEAH-box protein family | journal = J. Hum. Genet. | volume = 47 | issue = 12 | pages = 681–3 | year = 2002 | pmid = 12522690 | doi = 10.1007/s100380200104 | doi-access = free }}</ref><ref name="pmid16043509">{{cite journal |vauthors=Wang L, Lewis MS, Johnson AW | title = Domain interactions within the Ski2/3/8 complex and between the Ski complex and Ski7p | journal = RNA | volume = 11 | issue = 8 | pages = 1291–302 |date=August 2005 | pmid = 16043509 | pmc = 1370812 | doi = 10.1261/rna.2060405 }}</ref> These two relatives have a few particularly unique motifs{{which|date=October 2021}} that are conserved within their own family.<ref name="pmid10322435"/>

DEAD box, DEAH, and the SKI2 families are collectively referred to as '''DExD/H proteins'''.<ref name="pmid10322435">{{cite journal |vauthors=de la Cruz J, Kressler D, Linder P | title = Unwinding RNA in Saccharomyces cerevisiae: DEAD-box proteins and related families | journal = Trends Biochem. Sci. | volume = 24 | issue = 5 | pages = 192–8 |date=May 1999 | pmid = 10322435 | doi = 10.1016/S0968-0004(99)01376-6}}</ref> It is thought that each family has a specific role in RNA metabolism, for example both DEAD box and DEAH box proteins NTPase activities become stimulated by RNA, but DEAD box proteins use ATP and DEAH does not.<ref name="pmid12535527"/>

== Biological functions ==

DEAD box proteins are considered to be RNA helicases and many have been found to be required in cellular processes such as [[RNA]] metabolism, including nuclear [[transcription (genetics)|transcription]], [[RNA splicing|pre-mRNA splicing]], [[ribosome]] [[biogenesis]], nucleocytoplasmic transport, translation, RNA decay and organellar gene expression.<ref name="pmid10322435"/><ref name="pmid9862990">{{cite journal | vauthors = Aubourg S, Kreis M, Lecharny A | title = The DEAD box RNA helicase family in Arabidopsis thaliana | journal = Nucleic Acids Res. | volume = 27 | issue = 2 | pages = 628–36 |date=January 1999 | pmid = 9862990 | pmc = 148225 | doi = 10.1093/nar/27.2.628| url = }}</ref><ref name="pmid9476892">{{cite journal |vauthors=Staley JP, Guthrie C | title = Mechanical devices of the spliceosome: motors, clocks, springs, and things | journal = Cell | volume = 92 | issue = 3 | pages = 315–26 |date=February 1998 | pmid = 9476892 | doi = 10.1016/S0092-8674(00)80925-3| s2cid = 6208113 | doi-access = free }}</ref>

=== Pre-mRNA splicing ===
{{main article|RNA splicing}}
Pre-mRNA splicing requires rearrangements of five large RNP complexes, which are snRNPs U1, U2, U4, U5, and U6. DEAD box proteins are helicases that perform unwinding in an energy-dependent approach and are able to perform these snRNP rearrangements in a quick and efficient manner.<ref name="pmid16936318">{{cite journal | author = Linder P | title = Dead-box proteins: a family affair—active and passive players in RNP-remodeling | journal = Nucleic Acids Res. | volume = 34 | issue = 15 | pages = 4168–80 | year = 2006 | pmid = 16936318 | pmc = 1616962 | doi = 10.1093/nar/gkl468 }}</ref> There are three DEAD box proteins in the yeast system, Sub2, Prp28, and Prp5, which have been proven to be required for in vivo splicing.<ref name="pmid16936318"/> Prp5 has been shown to assist in a conformational rearrangement of U2 snRNA, which makes the branch point–recognition sequence of U2 available to bind the branch point sequence.<ref name="pmid7585243">{{cite journal |vauthors=Ghetti A, Company M, Abelson J | title = Specificity of Prp24 binding to RNA: a role for Prp24 in the dynamic interaction of U4 and U6 snRNAs | journal = RNA | volume = 1 | issue = 2 | pages = 132–45 |date=April 1995 | pmid = 7585243 | pmc = 1369067 }}</ref> Prp28 may have a role in recognizing the 5’ splice site and does not display RNA helicase activity, suggesting that other factors must be present in order to activate Prp28.<ref name="pmid7520570">{{cite journal |vauthors=Strauss EJ, Guthrie C | title = PRP28, a 'DEAD-box' protein, is required for the first step of mRNA splicing in vitro | journal = Nucleic Acids Res. | volume = 22 | issue = 15 | pages = 3187–93 |date=August 1994 | pmid = 7520570 | pmc = 310295 | doi = 10.1093/nar/22.15.3187}}</ref> DExD/H proteins have also been found to be required components in pre- mRNA splicing, in particular the DEAH proteins, Prp2, Prp16, Prp22, Prp43, and Brr213.<ref name="pmid12909336">{{cite journal |vauthors=Silverman E, Edwalds-Gilbert G, Lin RJ | title = DExD/H-box proteins and their partners: helping RNA helicases unwind | journal = Gene | volume = 312 | pages = 1–16 |date=July 2003 | pmid = 12909336 | doi = 10.1016/S0378-1119(03)00626-7}}</ref> As shown in the figure, DEAD box proteins are needed in the initial steps of spliceosome formation, while DEAH box proteins are indirectly required for the [[transesterification]]s, release of the mRNA, and recycling of the spliceosome complex9.

[[File:Spliceosome405.jpg|thumb|600px|The role of DEAD box proteins in pre-mRNA splicing. The orange text represents the DEAD box proteins.]]

=== Translation initiation ===
{{main article|Protein translation}}
The [[eIF4A]] translation initiation factor was the first DEAD box protein found to have an RNA-dependent [[ATPase]] activity. It has been proposed that this abundant protein helps in unwinding the secondary structure in the 5'-untranslated region.<ref name="pmid3065823"/> This can inhibit the scanning process of the small ribosomal subunit, if not unwound.<ref name="pmid3065823">{{cite book | author = Sonenberg N | title = Cap-binding proteins of eukaryotic messenger RNA: functions in initiation and control of translation| volume = 35 | pages = 173–207 | year = 1988 | pmid = 3065823 | doi = 10.1016/S0079-6603(08)60614-5| series = Progress in Nucleic Acid Research and Molecular Biology | isbn = 978-0-12-540035-0 }}</ref> [[Ded1]] is another DEAD box protein that is also needed for translation initiation, but its exact role in this process is still obscure.<ref name="pmid14763975">{{cite journal |vauthors=Berthelot K, Muldoon M, Rajkowitsch L, Hughes J, McCarthy JE | title = Dynamics and processivity of 40S ribosome scanning on mRNA in yeast | journal = Mol. Microbiol. | volume = 51 | issue = 4 | pages = 987–1001 |date=February 2004 | pmid = 14763975 | doi = 10.1046/j.1365-2958.2003.03898.x| doi-access = free }}</ref> [[Vasa gene|Vasa]], a DEAD box protein highly related to Ded1 plays a part in translation initiation by interacting with eukaryotic initiation factor 2 ([[eIF2]]).<ref name="pmid10678180">{{cite journal |vauthors=Carrera P, Johnstone O, Nakamura A, Casanova J, Jäckle H, Lasko P | title = VASA mediates translation through interaction with a Drosophila yIF2 homolog | journal = Mol. Cell | volume = 5 | issue = 1 | pages = 181–7 |date=January 2000 | pmid = 10678180 | doi = 10.1016/S1097-2765(00)80414-1| hdl = 11858/00-001M-0000-0012-F80E-6 | hdl-access = free }}</ref>

== See also ==
* [[DDX3X]]
* [[DEAD/DEAH box helicase]]
* [[RNA helicase]]
* [[Walker A motif]]
{{Clear}}

== References ==
{{Reflist|30em}}

[[Category:Protein domains]]

Tomes's process

2024-04-03T15:10:38Z

167.201.243.136: Added short description and inline citations needed template

{{short description|Histological feature of ameloblasts}}
{{inline citations needed|date=April 2024}}
'''Tomes's processes''' (also called '''Tomes processes''') are a [[histology|histologic]] landmark identified on an [[ameloblast]], cells involved in the production of [[tooth enamel]]. During the synthesis of enamel, the ameloblast moves away from the [[Tooth enamel|enamel]], forming a projection surrounded by the developing enamel. Tomes's processes are those projections and give the ameloblast a "picket-fence" appearance under a [[microscope]].

They are located on the secretory, basal, end of the ameloblast.

[[Terminal bar (histology)|Terminal bar]] apparatuses connect the Tomes's processes. [[Tonofilament]]s separate the developing enamel from the enamel organ. [[Gap junction]]s synchronize cell activation.

The body of the cell between the processes first deposits enamel, which will become the periphery of the enamel prisms, then the Tomes's process will infill the main body of the enamel prism. More than one ameloblast contributes to a single prism.

Tomes's processes are distinctly different from [[Tomes's fibers]], which are odontoblastic processes that occupy dentinal tubules.

==See also==
*[[Tooth]]
*[[Tomes's fibers]]
*[[John Tomes]]

==References==
*Cate, A. R. Ten. Oral Histology: development, structure, and function. 5th ed. 1998. {{ISBN|0-8151-2952-1}}.
*Ross, Michael H., Gordon I. Kaye, and Wojciech Pawlina. Histology: a text and atlas. 4th edition. 2003. {{ISBN|0-683-30242-6}}.

{{dentistry-stub}}
{{Tooth development}}
[[Category:Tooth development]]

NADPH—hemoprotein reductase

2024-03-25T17:26:21Z

167.201.243.136: Italicized scientific name

{{short description|Enzyme}}
{{enzyme
| Name = NADPH—hemoprotein reductase
| EC_number = 1.6.2.4
| CAS_number = 9023-03-4
| GO_code = 0003958
| image = 1j9z.jpg
| width = 270
| caption = NADPH-Cytochrome P450 reductase dimer, ''Rattus norvegicus''
}}
In [[enzymology]], a '''NADPH—hemoprotein reductase''' is an [[enzyme]] that [[catalysis|catalyzes]] the [[chemical reaction]]

:NADPH + H+ + n oxidized [[hemoprotein]] <math>\rightleftharpoons</math> NADP+ + n reduced hemoprotein

The three [[substrate (biochemistry)|substrate]]s of this enzyme are [[nicotinamide adenine dinucleotide phosphate|NADPH]], [[hydrogen ion|H+]], and [[oxidized hemoprotein]], whereas its two [[product (chemistry)|product]]s are [[nicotinamide adenine dinucleotide phosphate|NADP+]] and [[reduced hemoprotein]]. It has two [[cofactor (biochemistry)|cofactor]]s: [[flavin adenine dinucleotide]] (FAD) and [[flavin mononucleotide]] (FMN).

This enzyme belongs to the family of [[oxidoreductase]]s, specifically those acting on NADH or NADPH with a heme protein as acceptor. The [[List of enzymes|systematic name]] of this enzyme class is '''NADPH:hemoprotein oxidoreductase'''. Other names include '''cytochrome P450 reductase''', '''ferrihemoprotein P-450 reductase''', and '''NADPH-dependent cytochrome c reductase'''.

==Structural studies==

As of late 2007, 10 [[tertiary structure|structures]] have been solved for this class of enzymes, with [[Protein Data Bank|PDB]] accession codes {{PDB link|1AMO}}, {{PDB link|1B1C}}, {{PDB link|1J9Z}}, {{PDB link|1JA0}}, {{PDB link|1JA1}}, {{PDB link|1YQO}}, {{PDB link|1YQP}}, {{PDB link|2BF4}}, {{PDB link|2BN4}}, and {{PDB link|2BPO}}.

==References==
{{reflist|1}}
* {{cite journal |vauthors=Haas E, Horecker BL, Hogness TR | year = 1940 | title = The enzymatic reduction of cytochrome c, cytochrome c reductase | journal = J. Biol. Chem. | volume = 136 | pages = 747–774 | doi = 10.1016/S0021-9258(18)73034-2 | doi-access = free }}
* {{cite journal | author = Horecker BL | year = 1950 | title = Triphosphopyridine nucleotide-cytochrome c reductase in liver | journal = J. Biol. Chem. | volume = 183 | issue = 2 | pages = 593–605 | doi = 10.1016/S0021-9258(19)51185-1 | doi-access = free }}
* {{cite journal |vauthors=Lu AY, Junk KW, Coon MJ | year = 1969 | title = Resolution of the cytochrome P-450-containing omega-hydroxylation system of liver microsomes into three components | journal = J. Biol. Chem. | volume = 244 | pages = 3714–21 | pmid = 4389465 | issue = 13 | doi = 10.1016/S0021-9258(18)83427-5 | doi-access = free }}
* {{cite journal |vauthors=GIBSON QH, PALMER G, WHARTON DC | title = Studies on the Mechanism of Microsomal Triphosphopyridine Nucleotide-Cytochrome C Reductase | year = 1965 | journal = J. Biol. Chem. | volume = 240 | issue = 2 | pages = 921–31 | doi = 10.1016/S0021-9258(17)45262-8 | pmid = 14275154 | doi-access = free }}
* {{cite journal |author1=WILLIAMS CH Jr |author2=KAMIN H | year = 1962 | title = Microsomal triphosphopyridine nucleotide-cytochrome c reductase of liver | journal = J. Biol. Chem. | volume = 237 |issue=2 | pages = 587–95 |doi=10.1016/S0021-9258(18)93967-0 | pmid = 14007123 |doi-access=free }}
* {{cite journal |vauthors=Masters BS, Bilimoria MH, Kamin H, Gibson QH | author-link1=Bettie Sue Masters|year = 1965 | title = The mechanism of 1- and 2-electron transfers catalyzed by reduced triphosphopyridine nucleotide-cytochrome c reductase | journal = J. Biol. Chem. | volume = 240 | pages = 4081–8 | pmid = 4378860 | issue = 10 | doi = 10.1016/S0021-9258(18)97152-8 | doi-access = free }}
* {{cite journal |vauthors=Sevrioukova IF, Peterson JA | year = 1995 | title = NADPH-P-450 reductase: structural and functional comparisons of the eukaryotic and prokaryotic isoforms | journal = Biochimie | volume = 77 | pages = 562–72 | pmid = 8589067 | doi = 10.1016/0300-9084(96)88172-7 | issue = 7–8 }}
* {{cite journal |vauthors=Wang M, Roberts DL, Paschke R, Shea TM, Masters BS, Kim JJ | year = 1997 | title = Three-dimensional structure of NADPH-cytochrome P450 reductase: prototype for FMN- and FAD-containing enzymes | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 94 | pages = 8411–6 | pmid = 9237990 | doi = 10.1073/pnas.94.16.8411 | issue = 16 | pmc = 22938 | bibcode = 1997PNAS...94.8411W | doi-access = free }}
* {{cite journal |vauthors=Munro AW, Noble MA, Robledo L, Daff SN, Chapman SK | year = 2001 | title = Determination of the redox properties of human NADPH-cytochrome P450 reductase | journal = Biochemistry | volume = 40 | pages = 1956–63 | pmid = 11329262 | doi = 10.1021/bi001718u | issue = 7 }}
* {{cite journal |vauthors=Munro AW, Noble MA, Robledo L, Daff SN, Chapman SK | year = 2001 | title = Determination of the redox properties of human NADPH-cytochrome P450 reductase | journal = Biochemistry | volume = 40 | pages = 1956–63 | pmid = 11329262 | doi = 10.1021/bi001718u | issue = 7 }}
* {{cite journal | author = Scrutton NS | year = 2003 | title = Electron transfer in human cytochrome P450 reductase | journal = Biochem. Soc. Trans. | volume = 31 | pages = 497–501 | pmid = 12773143 | doi = 10.1042/BST0310497 | last2 = Grunau | first2 = A | last3 = Paine | first3 = M | last4 = Munro | first4 = AW | last5 = Wolf | first5 = CR | last6 = Roberts | first6 = GC | last7 = Scrutton | first7 = NS | issue = Pt 3 }}
* {{cite journal | author = Scrutton NS | year = 2003 | title = Electron transfer in human cytochrome P450 reductase | journal = Biochem. Soc. Trans. | volume = 31 | pages = 497–501 | pmid = 12773143 | doi = 10.1042/BST0310497 | last2 = Grunau | first2 = A | last3 = Paine | first3 = M | last4 = Munro | first4 = AW | last5 = Wolf | first5 = CR | last6 = Roberts | first6 = GC | last7 = Scrutton | first7 = NS | issue = Pt 3 }}

{{NADH or NADPH oxidoreductases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

{{DEFAULTSORT:NADPH-hemoprotein reductase}}
[[Category:EC 1.6.2]]
[[Category:NADPH-dependent enzymes]]
[[Category:Flavoproteins]]
[[Category:Enzymes of known structure]]

{{1.6-enzyme-stub}}

ALDH1L1

2024-03-21T16:14:55Z

167.201.243.136: Added wikilinks and declared acronym

{{short description|Protein-coding gene in the species Homo sapiens}}
{{cs1 config|name-list-style=vanc}}
{{Infobox_gene}}
'''10-formyltetrahydrofolate dehydrogenase''' is an [[enzyme]] that in humans is encoded by the ''ALDH1L1'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: ALDH1L1 aldehyde dehydrogenase 1 family, member L1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10840}}</ref>

The protein encoded by this gene catalyzes the conversion of [[10-formyltetrahydrofolate]], nicotinamide adenine dinucleotide phosphate ([[NADP]]), and water to [[tetrahydrofolate]], [[NADPH]], and carbon dioxide. The encoded protein belongs to the [[aldehyde dehydrogenase]] family and is responsible for [[formate]] oxidation in vivo. Deficiencies in this gene can result in an accumulation of formate and subsequent [[methanol poisoning]].<ref name="entrez"/>

==References==
{{reflist}}

==External links==
* {{UCSC gene info|ALDH1L1}}

==Further reading==
{{refbegin | 2}}
*{{cite journal | vauthors=Lee KM, Lan Q, Kricker A |title=One-carbon metabolism gene polymorphisms and risk of non-Hodgkin lymphoma in Australia. |journal=Hum. Genet. |volume=122 |issue= 5 |pages= 525–33 |year= 2007|pmid= 17891500 |doi= 10.1007/s00439-007-0431-2 |s2cid=21487646 |display-authors=etal|url=https://zenodo.org/record/1232733 }}
*{{cite journal | vauthors=Stevens VL, McCullough ML, Pavluck AL |title=Association of polymorphisms in one-carbon metabolism genes and postmenopausal breast cancer incidence. |journal=Cancer Epidemiol. Biomarkers Prev. |volume=16 |issue= 6 |pages= 1140–7 |year= 2007 |pmid= 17548676 |doi= 10.1158/1055-9965.EPI-06-1037 |display-authors=etal|doi-access= |s2cid=25945965 }}
*{{cite journal | vauthors=Lim U, Wang SS, Hartge P |title=Gene-nutrient interactions among determinants of folate and one-carbon metabolism on the risk of non-Hodgkin lymphoma: NCI-SEER case-control study. |journal=Blood |volume=109 |issue= 7 |pages= 3050–9 |year= 2007 |pmid= 17119116 |doi= 10.1182/blood-2006-07-034330 | pmc=1852210 |display-authors=etal}}
*{{cite journal | vauthors=Oleinik NV, Krupenko SA |title=Ectopic expression of 10-formyltetrahydrofolate dehydrogenase in A549 cells induces G1 cell cycle arrest and apoptosis. |journal=Mol. Cancer Res. |volume=1 |issue= 8 |pages= 577–88 |year= 2004 |pmid= 12805405 }}
*{{cite journal | vauthors=Strausberg RL, Feingold EA, Grouse LH |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |bibcode=2002PNAS...9916899M |display-authors=etal|doi-access=free }}
*{{cite journal | vauthors=Krupenko SA, Oleinik NV |title=10-formyltetrahydrofolate dehydrogenase, one of the major folate enzymes, is down-regulated in tumor tissues and possesses suppressor effects on cancer cells. |journal=Cell Growth Differ. |volume=13 |issue= 5 |pages= 227–36 |year= 2002 |pmid= 12065246 }}
*{{cite journal | vauthors=Hong M, Lee Y, Kim JW |title=Isolation and characterization of cDNA clone for human liver 10-formyltetrahydrofolate dehydrogenase. |journal=Biochem. Mol. Biol. Int. |volume=47 |issue= 3 |pages= 407–15 |year= 1999 |pmid= 10204077 |doi= 10.1080/15216549900201433|s2cid=10950424 |display-authors=etal|doi-access=free }}
*{{cite journal | vauthors=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1–2 |pages= 149–56 |year= 1997 |pmid= 9373149 |doi=10.1016/S0378-1119(97)00411-3 |display-authors=etal}}
*{{cite journal | vauthors=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides |journal=Gene |volume=138 |issue= 1–2 |pages= 171–4 |year= 1994 |pmid= 8125298 |doi=10.1016/0378-1119(94)90802-8 }}
*{{cite journal | vauthors=Champion KM, Cook RJ, Tollaksen SL, Giometti CS |title=Identification of a heritable deficiency of the folate-dependent enzyme 10-formyltetrahydrofolate dehydrogenase in mice |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue= 24 |pages= 11338–42 |year= 1994 |pmid= 7972060 |doi=10.1073/pnas.91.24.11338 | pmc=45226 |bibcode=1994PNAS...9111338C |doi-access=free }}
*{{cite journal | vauthors=Johlin FC, Swain E, Smith C, Tephly TR |title=Studies on the mechanism of methanol poisoning: purification and comparison of rat and human liver 10-formyltetrahydrofolate dehydrogenase |journal=Mol. Pharmacol. |volume=35 |issue= 6 |pages= 745–50 |year= 1989 |pmid= 2733692 }}
{{refend}}
{{PDB Gallery|geneid=10840}}
{{Aldehyde dehydrogenases}}

{{gene-3-stub}}

AIR synthetase (FGAM cyclase)

2024-03-15T16:03:16Z

167.201.243.136: /* Purine synthesis */ Added main article template

{{infobox enzyme
| Name = Phosphoribosylformylglycinamidine cyclo-ligase
| EC_number = 6.3.3.1
| CAS_number = 9023-53-4
| GO_code = 0004641
| image =
| width =
| caption =
}}

'''Phosphoribosylformylglycinamidine cyclo-ligase''' ('''AIR synthetase''') is the fifth [[enzyme]] ({{EnzExplorer|6.3.3.1}}) in the ''de novo'' synthesis of [[purine]] [[nucleotides]]. It catalyzes the reaction to form [[5-aminoimidazole ribotide]] (AIR) from [[formylglycinamidine-ribonucleotide]] FGAM. This reaction closes the ring and produces a 5-membered imidazole ring of the purine nucleus (AIR):

[[File:AIR Synthetase.svg|480px]]

<div align=center>ATP + 2-(formamido)-N1-(5-phospho-β-D-ribosyl)acetamidine <math>\rightleftharpoons</math> ADP + 5-amino-1-(5-phospho-β-D-ribosyl)imidazole + phosphate + {{chem|H|+}}</div>

AIR synthetase catalyzes the transfer of the oxygen of the formyl group to phosphate. It is a sequential mechanism in which ATP binds first to the enzyme and ADP is released last. This enzyme hydrolyzes ATP to activate the oxygen of the amide in order to carry out a nucleophilic attack by nitrogen. In humans and many other animals, this enzyme is contained within the [[trifunctional purine biosynthetic protein adenosine-3]] polypeptide.

== Nomenclature ==
The [[List of enzymes|systematic name]] of this enzyme class is 2-(formamido)-N1-(5-phosphoribosyl)acetamidine cyclo-ligase (ADP-forming). Other names in common use include:
* AIR synthetase,
* 5'-aminoimidazole ribonucleotide synthetase,
* 2-(formamido)-1-N-(5-phosphoribosyl)acetamidine cyclo-ligase (ADP-forming),
* phosphoribosylaminoimidazole synthetase, and
* phosphoribosylformylglycinamidine cyclo-ligase.

== Purine synthesis ==
{{main article|Purine biosynthesis}}
Purines are one of the two types of nitrogenous heterocyclic bases, which are one of the three components of the nucleotides that make up nucleic acids. Synthesis can be de novo or salvage — AIR synthetase is a component of the ''de novo'' pathway. The first committed step of the de novo pathway begins with phosphoribosyl pyrophosphate (PRPP) and the end product is inosine monophosphate (IMP). IMP is eventually converted to either AMP or GMP purines. The purine ring structure is composed by the attachment of 1 or 2 atoms at a time to the ribose sugar. The ''de novo'' pathway tends to be conserved across most organisms.

== Cowpea AIR synthetase ==
AIR synthetase is found in both [[mitochondria]] and [[plastid]]s; the mitochondrial form has 5 more amino acids than the plastid form.<ref name="pmid12644656">{{cite journal | vauthors = Goggin DE, Lipscombe R, Fedorova E, Millar AH, Mann A, Atkins CA, Smith PM | title = Dual Intracellular Localization and Targeting of Aminoimidazole Ribonucleotide Synthetase in Cowpea | journal = Plant Physiol. | volume = 131 | issue = 3 | pages = 1033–41 |date=March 2003 | pmid = 12644656 | pmc = 166869 | doi = 10.1104/pp.102.015081 }}</ref> The enzyme is encoded by a single gene in cowpeas despite the fact that it exists in different forms in plastids and mitochondria. This suggests that the different versions may be derived from a single transcript. One study proposes that there is tight transcriptional control of pur5, the gene encoding AIR synthetase.<ref name="pmid9520274">{{cite journal | vauthors = Smith PM, Mann AJ, Goggin DE, Atkins CA | title = AIR synthetase in cowpea nodules: a single gene product targeted to two organelles? | journal = Plant Mol. Biol. | volume = 36 | issue = 6 | pages = 811–20 |date=April 1998 | pmid = 9520274 | doi = 10.1023/A:1005969830314}}</ref>

== References ==
{{reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Levenberg B, Buchanan JM | year = 1957 | title = Biosynthesis of the purines. XII. Structure, enzymatic synthesis, and metabolism of 5-amino-imidazole ribotide | journal = J. Biol. Chem. | volume = 224 | pages = 1005–18 | pmid = 13405929 | issue = 2 }}
* {{cite journal | vauthors = Levenberg B, Buchanan JM | year = 1957 | title = Biosynthesis of the purines. XIII. Structure, enzymatic synthesis, and metabolism of (alpha-N-formyl)-glycinamidine ribotide | journal = J. Biol. Chem. | volume = 224 | pages = 1019–27 | pmid = 13405930 | issue = 2 }}
* {{cite journal |vauthors =Li C, Kappock TJ, Stubbe J, Weaver TM, Ealick SE |title=X-ray crystal structure of aminoimidazole ribonucleotide synthetase (PurM), from the Escherichia coli purine biosynthetic pathway at 2.5 A resolution |journal=Structure |volume=7 |issue=9 |pages=1155–66 |year=1999 |pmid=10508786 |doi=10.1016/S0969-2126(99)80182-8|doi-access=free }}
{{refend}}

==External links==
* {{MeshName|AIR+synthetase}}

{{Nucleotide metabolism enzymes}}
{{Ligases CO CS and CN}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

[[Category:EC 6.3.3]]

Negri body

2024-03-14T16:18:06Z

167.201.243.136: /* History and use as a Rabies Diagnosis */ Shortened section header

{{Short description|Positive indicator of rabies infection}}
[[File:Histopathology of Negri bodies in rabies encephalitis.png|thumb|Histopathology of Negri bodies in rabies encephalitis.]]
[[Image:Rabies Virus EM PHIL 1876.JPG|thumb|250px|Micrograph with numerous rabies virions (small dark-grey rod-like particles) and Negri bodies, larger [[pathognomonic]] cellular [[inclusion bodies]] of rabies infection.]]

'''Negri bodies''' are [[eosinophilic]], sharply outlined, [[pathognomonic]] [[inclusion bodies]] (2–10 [[micrometre|μm]] in diameter) found in the [[cytoplasm]] of certain [[nerve cell]]s containing the [[Rabies virus|virus of rabies]], especially in [[pyramidal cell]]s<ref name=":0">{{Cite web|url=https://www.sketchymedical.com/sections/viruses-2-3-rhabdovirus|title=2.3 Rhabdovirus|last=Sketchy Group, LLC|website=www.sketchymedical.com|language=en|access-date=2017-04-12|archive-url=https://web.archive.org/web/20170413234842/https://www.sketchymedical.com/sections/viruses%2D2%2D3%2Drhabdovirus|archive-date=2017-04-13|url-status=dead}}</ref> within [[Ammon's horn]] of the [[hippocampus]]. They are also often found in the [[Purkinje cell]]s<ref name=":0" /> of the [[cerebellar cortex]] from postmortem brain samples of [[rabies]] victims. They consist of ribonuclear proteins produced by the virus.<ref>{{cite journal|last1=Lahaye|first1=Xavier|last2=Vidy|first2=Aurore|last3=Pomier|first3=Carole|last4=Obiang|first4=Linda|last5=Harper|first5=Francis|last6=Gaudin|first6=Yves|last7=Blondel|first7=Danielle|title=Functional Characterization of Negri Bodies (NBs) in Rabies Virus-Infected Cells: Evidence that NBs Are Sites of Viral Transcription and Replication|journal=Journal of Virology|date=15 August 2009|volume=83|issue=16|pages=7948–7958|doi=10.1128/JVI.00554-09|pmid=19494013|language=en|issn=0022-538X|pmc=2715764}}</ref>

They are named for [[Adelchi Negri]].<ref>{{WhoNamedIt|synd|2491}}</ref>

==History and significance==
Adelchi Negri, an assistant pathologist working in the laboratory of [[Camillo Golgi]], observed these inclusions in rabbits and dogs with [[rabies]]. These findings were presented in 1903 at a meeting of the Società Medico-Chirurgica of Pavia. The American pathologist [[Anna Wessels Williams]] made the same discovery,<ref>{{Cite web|url=https://cfmedicine.nlm.nih.gov/physicians/biography_331.html|title=Changing the Face of Medicine|website=NCBI}}</ref> but because Negri published his results<ref>{{Cite journal|last=Negri|first=Adelchi|date=1904|title=Contributo allo studio dell'eziologia della rabbia|journal=Bollettino della Società Medico-chirurgica di Pavia|volume=2|pages=88–115}}</ref> first, the bodies bear his name.

Negri was convinced the inclusions were a parasitic [[Protozoa|protozoon]] and the [[Cause (medicine)|etiologic agent]] of rabies. Later that same year, however, [[Paul Remlinger]] and [[Rifat-Bey Frasheri]] in [[Constantinople]] and, separately, [[Alfonso di Vestea]] in [[Naples]] showed that the etiologic agent of rabies is a filterable [[virus]]. Negri continued until 1909 to try to prove that the intraneuronal inclusions named after him corresponded to steps in the developmental cycle of a protozoan.

In spite of his incorrect etiologic hypothesis, Negri's discovery represented a breakthrough in the rapid diagnosis of rabies, and the detection of Negri bodies, using a method developed by [[Anna Wessels Williams]], remained the primary way to detect rabies for the next thirty years.<ref>{{cite journal |last1=Henry |first1=Ronnie |last2=Murphy |first2=Frederick R. |date=2017 |title=Etymologia: Negri Bodies |journal= Emerg Infect Dis |volume=23 |issue=9 |pages=1461 |doi=10.3201/eid2309.ET2309 |quote=citing public domain text from the CDC |pmc=5572856 }}</ref>

==References==
{{Reflist}}

==External links==
* [http://pathmicro.med.sc.edu/virol/rabies.htm Slide at pathmicro.med.sc.edu – see bottom]
* [https://www.youtube.com/watch?v=NP5CYphae5Y See pathology video of Negri bodies]

{{Infectious blood tests}}

{{DEFAULTSORT:Negri Bodies}}
[[Category:Histopathology]]
[[Category:Rabies]]
[[Category:Hippocampus (brain)]]
[[Category:Neuropathology]]

Thiolase

2024-02-26T15:10:24Z

167.201.243.136: /* Biological function */ Added citation

{{Short description|Enzymes}}
{{Distinguish|Acyl-CoA:cholesterol acyltransferase|Acetyl-CoA C-acyltransferase}}
{{Pfam box
| Symbol = Thiolase_N
| Name = Thiolase, N-terminal domain
| image =
| width =
| caption =
| Pfam= PF00108
| InterPro= IPR002155
| SMART=
| Prosite = PDOC00092
| SCOP = 1pxt
| TCDB =
| CDD = cd00751
| OPM family=
| OPM protein=
}}
{{Pfam_box
| Symbol = Thiolase_C
| Name = Thiolase, C-terminal domain
| image =
| width =
| caption =
| Pfam= PF02803
| InterPro= IPR002155
| SMART=
| Prosite = PDOC00092
| SCOP = 1pxt
| TCDB =
| OPM family=
| OPM protein=
}}
[[Image:Mevalonate pathway.png|350px|thumb|Mevalonate pathway]]

'''Thiolases''', also known as '''acetyl-coenzyme A acetyltransferases''' ('''ACAT'''), are enzymes which convert two units of [[acetyl-CoA]] to [[acetoacetyl CoA]] in the [[mevalonate pathway]].

Thiolases are ubiquitous [[enzymes]] that have key roles in many vital biochemical pathways, including the [[beta oxidation]] pathway of fatty acid degradation and various biosynthetic pathways.<ref name="pmid2775734">{{cite journal |vauthors=Thompson S, Mayerl F, Peoples OP, Masamune S, Sinskey AJ, Walsh CT | title = Mechanistic studies on beta-ketoacyl thiolase from Zoogloea ramigera: identification of the active-site nucleophile as Cys89, its mutation to Ser89, and kinetic and thermodynamic characterization of wild-type and mutant enzymes | journal = Biochemistry | volume = 28 | issue = 14 | pages = 5735–42 |date=July 1989 | pmid = 2775734 | doi = 10.1021/bi00440a006 }}</ref> Members of the thiolase family can be divided into two broad categories: degradative thiolases (EC 2.3.1.16) and biosynthetic thiolases (EC 2.3.1.9). These two different types of thiolase are found both in [[eukaryotes]] and in [[prokaryotes]]: acetoacetyl-CoA thiolase (EC:2.3.1.9) and [[Acetyl-CoA C-acyltransferase|3-ketoacyl-CoA thiolase]] (EC:2.3.1.16). [[3-ketoacyl-CoA]] thiolase (also called thiolase I) has a broad chain-length specificity for its substrates and is involved in degradative pathways such as fatty acid beta-oxidation. Acetoacetyl-CoA thiolase (also called thiolase II) is specific for the [[thiolysis]] of [[acetoacetyl-CoA]] and involved in biosynthetic pathways such as [[beta-hydroxybutyric acid]] synthesis or [[steroid]] biogenesis.

The formation of a carbon–carbon bond is a key step in the biosynthetic pathways by which [[fatty acids]] and [[polyketide]] are made. The thiolase superfamily [[enzymes]] catalyse the carbon–carbon-bond formation via a thioester-dependent [[Claisen condensation]]<ref name="pmid12430724">{{cite journal |vauthors=Heath RJ, Rock CO | title = The Claisen condensation in biology | journal = Nat Prod Rep | volume = 19 | issue = 5 | pages = 581–96 |date=October 2002 | pmid = 12430724 | doi = 10.1039/b110221b}}</ref> reaction mechanism.<ref name="pmid16356722">{{cite journal |vauthors=Haapalainen AM, Meriläinen G, Wierenga RK | title = The thiolase superfamily: condensing enzymes with diverse reaction specificities | journal = Trends Biochem. Sci. | volume = 31 | issue = 1 | pages = 64–71 |date=January 2006 | pmid = 16356722 | doi = 10.1016/j.tibs.2005.11.011 }}</ref>

== Function ==

'''Thiolases''' are [[Protein family|a family]] of evolutionarily related [[enzymes]]. Two different types of thiolase<ref name="pmid1755959">{{cite journal |vauthors=Baker ME, Billheimer JT, Strauss JF | title = Similarity between the amino-terminal portion of mammalian 58-kD sterol carrier protein (SCPx) and Escherichia coli acetyl-CoA acyltransferase: evidence for a gene fusion in SCPx | journal = DNA Cell Biol. | volume = 10 | issue = 9 | pages = 695–8 |date=November 1991 | pmid = 1755959 | doi = 10.1089/dna.1991.10.695 }}</ref><ref name="pmid2191949">{{cite journal |vauthors=Yang SY, Yang XY, Healy-Louie G, Schulz H, Elzinga M | title = Nucleotide sequence of the fadA gene. Primary structure of 3-ketoacyl-coenzyme A thiolase from Escherichia coli and the structural organization of the fadAB operon | journal = J. Biol. Chem. | volume = 265 | issue = 18 | pages = 10424–9 |date=June 1990 | pmid = 2191949 }}</ref><ref name="pmid1354266">{{cite journal |vauthors=Igual JC, González-Bosch C, Dopazo J, Pérez-Ortín JE | title = Phylogenetic analysis of the thiolase family. Implications for the evolutionary origin of peroxisomes | journal = J. Mol. Evol. | volume = 35 | issue = 2 | pages = 147–55 |date=August 1992 | pmid = 1354266 | doi = 10.1007/BF00183226 | s2cid = 39746646 }}</ref> are found both in eukaryotes and in prokaryotes: [[Acetyl-CoA C-acetyltransferase|acetoacetyl-CoA thiolase]] ({{EC number|2.3.1.9}}) and [[Acetyl-CoA C-acyltransferase|3-ketoacyl-CoA thiolase]] ({{EC number|2.3.1.16}}). 3-ketoacyl-CoA thiolase (also called thiolase I) has a broad chain-length specificity for its substrates and is involved in degradative pathways such as fatty acid beta-oxidation. Acetoacetyl-CoA thiolase (also called thiolase II) is specific for the thiolysis of [[acetoacetyl-CoA]] and involved in biosynthetic pathways such as poly beta-hydroxybutyrate synthesis or steroid biogenesis.

In eukaryotes, there are two forms of 3-ketoacyl-CoA thiolase: one located in the mitochondrion and the other in peroxisomes.

There are two conserved cysteine residues important for thiolase activity. The first located in the N-terminal section of the enzymes are involved in the formation of an acyl-enzyme intermediate; the second located at the C-terminal extremity is the active site base involved in deprotonation in the condensation reaction.

== Isozymes ==
{| class="wikitable"
|-
! EC number !! Name !! Alternate name !! Isozymes !! Subcellular distribution
|-
| rowspan="2" | {{EC number|2.3.1.9}} || rowspan="2" | [[Acetyl-CoA C-acetyltransferase]] || rowspan="2" | thiolase II; Acetoacetyl-CoA thiolase || [[ACAT1]] || mitochondrial
|-
| [[ACAT2]] || cytosolic
|-
| rowspan="3" | {{EC number|2.3.1.16}} || rowspan="3" | [[Acetyl-CoA C-acyltransferase]] || rowspan="3" | thiolase I; 3-Ketoacyl-CoA thiolase; β-Ketothiolase 3-KAT || [[ACAA1]] || peroxisomal
|-
| [[ACAA2]] || mitochondrial
|-
| [[HADHB]] || mitochondrial

|-
| {{EC number|2.3.1.154}} || [[Propionyl-CoA C2-trimethyltridecanoyltransferase]] || 3-Oxopristanoyl-CoA thiolase || ||
|-
| {{EC number|2.3.1.174}} || [[3-oxoadipyl-CoA thiolase|3-Oxoadipyl-CoA thiolase]] || β-Ketoadipyl-CoA thiolase || ||
|-
| {{EC number|2.3.1.176}} || [[Propanoyl-CoA C-acyltransferase]] || Peroxisomal thiolase 2 || [[SCP2]] || peroxisomal/cytosolic
|}

Mammalian nonspecific lipid-transfer protein (nsL-TP) (also known as [[SCP2|sterol carrier protein 2]]) is a protein which seems to exist in two different forms: a 14 Kd protein (SCP-2) and a larger 58 Kd protein (SCP-x). The former is found in the cytoplasm or the mitochondria and is involved in lipid transport; the latter is found in [[peroxisomes]]. The C-terminal part of SCP-x is identical to SCP-2 while the N-terminal portion is evolutionary related to thiolases.<ref name="pmid1354266"/>

== Mechanism ==

[[Image:Thioalse Reaction Catalysis.gif|500px|thumb|Reaction catalyzed by thiolase]]

[[Thioesters]] are more reactive than oxygen esters and are common intermediates in fatty-acid metabolism.<ref>{{cite book |title=Enzymatic reaction mechanisms |publisher=W. H. Freeman |location=San Francisco |year=1979 |isbn=978-0-7167-0070-8 }}</ref> These thioesters are made by conjugating the fatty acid with the free SH group of the [[pantetheine]] moiety of either [[coenzyme A]] (CoA) or [[acyl carrier protein]] (ACP).

All thiolases, whether they are biosynthetic or degradative in vivo, preferentially catalyze the degradation of 3-ketoacyl-CoA to form acetyl-CoA and a shortened acyl-CoA species, but are also capable of catalyzing the reverse [[Claisen condensation]] reaction (reflecting the negative Gibbs energy change of the degradation, which is independent of the thiolase catalyzing the reaction). It is well established from studies on the biosynthetic thiolase from Z. ramigera that the thiolase reaction occurs in two steps and follows ping-pong kinetics.<ref>{{cite journal |last1= Masamune |first1= Satoru |last2= Walsh |first2=Christopher T. |last3= Gamboni |year=1989 |first3= Remo |last4= Thompson |first4= Stuart |last5= Davis |first5= Jeffrey T. |last6= Williams |first6= Simon F. |last7= Peoples |first7= Oliver P. |last8= Sinskey |first8= Anthony J. |last9= Walsh |first9= Christopher T. |title=Bio-Claisen condensation catalyzed by thiolase from Zoogloea ramigera. Active site cysteine residues |journal=J. Am. Chem. Soc. |volume=111 |issue=5 |pages=1879, 1991 |doi= 10.1021/ja00187a053 }}</ref> In the first step of both the degradative and biosynthetic reactions, the nucleophilic Cys89 (or its equivalent) attacks the acyl-CoA (or 3-ketoacyl-CoA) substrate, leading to the formation of a covalent acyl-enzyme intermediate.<ref name="pmid6114098">{{cite journal |vauthors=Gilbert HF, Lennox BJ, Mossman CD, Carle WC | title = The relation of acyl transfer to the overall reaction of thiolase I from porcine heart | journal = J. Biol. Chem. | volume = 256 | issue = 14 | pages = 7371–7 |date=July 1981 | pmid = 6114098 }}</ref> In the second step, the addition of CoA (in the degradative reaction) or acetyl-CoA (in the biosynthetic reaction) to the acyl–enzyme intermediate triggers the release of the product from the enzyme.<ref>{{cite journal |vauthors=Mathieu M, Modis Y, Zeelen JP, etal |title=The 1.8 A crystal structure of the dimeric peroxisomal 3-ketoacyl-CoA thiolase of Saccharomyces cerevisiae: implications for substrate binding and reaction mechanism |journal=[[J. Mol. Biol.]] |volume=273 |issue=3 |pages=714–28 |date=October 1997 |pmid=9402066 |doi=10.1006/jmbi.1997.1331|doi-access=free }}</ref> Each of the tetrahedral reaction intermediates that occur during transfer of an acetyl group to and from the nucleophilic cysteine, respectively, have been observed in X-ray crystal structures of biosynthetic thiolase from A. fumigatus.<ref>{{cite journal |last1=Marshall |first1=Andrew C. |last2=Bond |first2=Charles S. |last3=Bruning |first3=John B. |title=Structure of Aspergillus fumigatus Cytosolic Thiolase: Trapped Tetrahedral Reaction Intermediates and Activation by Monovalent Cations. |journal=ACS Catalysis |date=January 25, 2018 |volume=8 |issue=3 |pages=1973–1989 |doi=10.1021/acscatal.7b02873 |hdl=2440/113865 |hdl-access=free }}</ref>

[[Image: Thiolase Mechanisim.gif|thumb|Thiolase Mechanism. The two-step, ping-pong mechanism for the thiolase
reaction. Red arrows indicate the biosynthetic reaction; Black arrows trace the degradative reaction. In both directions, the reaction is initiated by the nucleophilic attack of Cys89 on the substrate to form a covalent acetyl–enzyme intermediate. Cys89 is activated for nucleophilic attack by His348, which abstracts the sulfide proton of Cys89. In the second step of both the biosynthetic and degradative reactions, the substrate nucleophilically attacks the acetyl–enzyme intermediate to yield the final product and free enzyme. This nucleophilic attack is activated by Cys378, which abstracts a proton from the substrate. ]]

== Structure ==

Most enzymes of the thiolase superfamily are [[protein dimer|dimers]]. However, monomers have not been observed. [[Tetrameric protein|Tetramers]] are observed only in the thiolase subfamily and, in these cases, the dimers have dimerized to become tetramers. The crystal structure of the tetrameric biosynthetic thiolase from ''[[Zoogloea ramigera]]'' has been determined at 2.0 Å resolution. The structure contains a striking and novel ‘cage-like’ tetramerization motif, which allows for some hinge motion of the two tight dimers with respect to each other. The enzyme tetramer is acetylated at Cys89 and has a CoA molecule bound in each of its
active-site pockets.<ref>{{cite journal |vauthors=Modis Y, Wierenga RK |title=A biosynthetic thiolase in complex with a reaction intermediate: the crystal structure provides new insights into the catalytic mechanism |journal=Structure |volume=7 |issue=10 |pages=1279–90 |date=October 1999 |pmid=10545327 |doi= 10.1016/S0969-2126(00)80061-1|doi-access=free }}</ref>

== Biological function ==

In [[eukaryotic]] cells, especially in mammalian cells, thiolases exhibit diversity in intracellular localization related to their metabolic functions as well as in substrate specificity. For example, they contribute to fatty-acid β-oxidation in [[peroxisomes]] and [[mitochondria]], [[ketone body]] metabolism in mitochondria,<ref>{{cite journal |author=Middleton B |title=The oxoacyl-coenzyme A thiolases of animal tissues |journal=[[Biochem. J.]] |volume=132 |issue=4 |pages=717–30 |date=April 1973 |pmid=4721607 |pmc=1177647 |doi= 10.1042/bj1320717}}</ref> and the early steps of [[mevalonate pathway]] in peroxisomes and [[cytoplasm]].<ref>{{cite journal |vauthors=Hovik R, Brodal B, Bartlett K, Osmundsen H |title=Metabolism of acetyl-CoA by isolated peroxisomal fractions: formation of acetate and acetoacetyl-CoA |journal=[[J. Lipid Res.]] |volume=32 |issue=6 |pages=993–9 |date=June 1991 |pmid=1682408 |url=http://www.jlr.org/cgi/pmidlookup?view=long&pmid=1682408}}</ref> In addition to biochemical investigations, analyses of genetic disorders have made clear the basis of their functions.<ref>{{cite journal |vauthors=Middleton B, Bartlett K |title=The synthesis and characterisation of 2-methylacetoacetyl coenzyme A and its use in the identification of the site of the defect in 2-methylacetoacetic and 2-methyl-3-hydroxybutyric aciduria |journal=[[Clin. Chim. Acta]] |volume=128 |issue=2–3 |pages=291–305 |date=March 1983 |pmid=6133656 |doi= 10.1016/0009-8981(83)90329-7}}</ref> Genetic studies have identified a three-thiolase system in the yeast ''[[Candida tropicalis]]'', which has thiolase activity in peroxisomes, where it may participate in beta oxidation, and in the cytosol, where it participates in the mevalonate pathway.<ref>{{cite journal |vauthors=Kanayama N, Ueda M, Atomi H, Tanaka A |title=Genetic evaluation of physiological functions of thiolase isoenzymes in the n-alkalane-assimilating yeast Candida tropicalis |journal=[[J. Bacteriol.]] |volume=180 |issue=3 |pages=690–8 |date=February 1998 |pmid=9457876 |pmc=106940 |doi= 10.1128/JB.180.3.690-698.1998}}</ref><ref>{{cite journal|vauthors=Ueda M, Kanayama N, Tanaka A|title=Genetic evaluation of peroxisomal and cytosolic acetoacetyl-CoA thiolase isozymes in n-alkane-assimilating diploid yeast, Candida tropicalis|journal=Cell Biochemistry and Biophysics|volume=32|issue=Spring|year=2000|pages=285-290|doi=10.1385/cbb:32:1-3:285|pmid=11330060}}</ref> Thiolase is of central importance in key enzymatic pathways such as fatty-acid, steroid and polyketide synthesis. The detailed understanding of its structural biology is of great medical relevance, for example, for a better understanding of the diseases caused by genetic deficiencies of these enzymes and for the development of new antibiotics.<ref name="pmid11050088">{{cite journal |vauthors=Price AC, Choi KH, Heath RJ, Li Z, White SW, Rock CO | title = Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism | journal = J. Biol. Chem. | volume = 276 | issue = 9 | pages = 6551–9 |date=March 2001 | pmid = 11050088 | doi = 10.1074/jbc.M007101200 | doi-access = free }}</ref> Harnessing the complicated catalytic versatility of the polyketide synthases for the synthesis of biologically and medically relevant natural products is also an important future perspective of the studies of the enzymes of this superfamily.<ref name="pmid15286722">{{cite journal |vauthors=Keatinge-Clay AT, Maltby DA, Medzihradszky KF, Khosla C, Stroud RM | title = An antibiotic factory caught in action | journal = Nat. Struct. Mol. Biol. | volume = 11 | issue = 9 | pages = 888–93 |date=September 2004 | pmid = 15286722 | doi = 10.1038/nsmb808 | s2cid = 12394083 }}</ref>

== Disease relevance ==

Mitochondrial acetoacetyl-CoA thiolase deficiency, known earlier as [[beta-ketothiolase deficiency|β-ketothiolase deficiency]],<ref name="pmid4143539">{{cite journal |vauthors=Daum RS, Lamm PH, Mamer OA, Scriver CR | title = A "new" disorder of isoleucine catabolism | journal = Lancet | volume = 2 | issue = 7737 | pages = 1289–90 |date=December 1971 | pmid = 4143539 | doi =10.1016/S0140-6736(71)90605-2 | url = http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=50299}}</ref> is an [[inborn error of metabolism]] involving [[Isoleucine#Catabolism|isoleucine catabolism]] and ketone body metabolism. The major clinical manifestations of this disorder are intermittent [[ketoacidosis]] but the long-term clinical consequences, apparently benign, are not well documented. Mitochondrial acetoacetyl-CoA thiolase deficiency is easily diagnosed by urinary organic acid analysis and can be confirmed by enzymatic analysis of cultured skin fibroblasts or blood leukocytes.<ref name="isbn0-07-913035-6">{{cite book |vauthors=Mitchell GA, Fukao T |veditors=Scriver CR, Beaudet AL, Sly WS, Valle D | title = The metabolic & molecular bases of inherited disease | publisher = McGraw-Hill | location = New York | year = 2001 | pages = 2326–2356 | isbn = 978-0-07-913035-8 | chapter = Inborn errors of ketone body metabolism }}</ref>

β-Ketothiolase Deficiency has a variable presentation. Most affected patients present between 5 and 24 months of age with symptoms of severe ketoacidosis. Symptoms can be initiated by a dietary protein load, infection or fever. Symptoms progress from vomiting to dehydration and ketoacidosis.<ref name="pmid4812006">{{cite journal |vauthors=Hillman RE, Keating JP | title = Beta-ketothiolase deficiency as a cause of the "ketotic hyperglycinemia syndrome" | journal = Pediatrics | volume = 53 | issue = 2 | pages = 221–5 |date=February 1974 | pmid = 4812006 }}</ref> Neutropenia and thrombocytopenia may be present, as can moderate hyperammonemia. Blood glucose is typically normal, but can be low or high in acute episodes.<ref name="pmid36452">{{cite journal |vauthors=Robinson BH, Sherwood WG, Taylor J, Balfe JW, Mamer OA | title = Acetoacetyl CoA thiolase deficiency: a cause of severe ketoacidosis in infancy simulating salicylism | journal = J. Pediatr. | volume = 95 | issue = 2 | pages = 228–33 |date=August 1979 | pmid = 36452 | doi = 10.1016/S0022-3476(79)80658-7}}</ref> Developmental delay may occur, even before the first acute episode, and bilateral striatal [[necrosis]] of the [[basal ganglia]] has been seen on brain [[MRI]].

==References==
{{reflist|2}}

==External links==
* {{MeshName|Acetyl-CoA+C-Acetyltransferase}}
* {{PDBe-KB2|P28790|3-ketoacyl-CoA thiolase}}
* {{PDBe-KB2|Q56WD9|3-ketoacyl-CoA thiolase 2, peroxisomal }}

{{Acyltransferases}}
{{Mevalonate pathway}}
{{InterPro content|IPR002155}}

[[Category:Protein domains]]

IMPDH1

2024-02-23T14:50:09Z

167.201.243.136: /* Clinical significance */ Italicized gene name

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{cs1 config|name-list-style=vanc}}
{{Infobox_gene}}
'''Inosine-5'-monophosphate dehydrogenase 1''', also known as '''IMP dehydrogenase 1''', is an [[enzyme]] that in humans is encoded by the ''IMPDH1'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: IMP (inosine monophosphate) dehydrogenase 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3614}}</ref><ref name="pmid1969416">{{cite journal |vauthors=Natsumeda Y, Ohno S, Kawasaki H, Konno Y, Weber G, Suzuki K | title = Two distinct cDNAs for human IMP dehydrogenase | journal = J. Biol. Chem. | volume = 265 | issue = 9 | pages = 5292–5 |date=March 1990 | doi = 10.1016/S0021-9258(19)34120-1 | pmid = 1969416 | doi-access = free }}</ref>

== Function ==

IMP dehydrogenase 1 acts as a homotetramer to regulate cell growth. IMPDH1 is an enzyme that catalyzes the synthesis of [[xanthosine monophosphate|xanthine monophosphate]] (XMP) from [[inosinic acid|inosine-5'-monophosphate]] (IMP). This is the rate-limiting step in the de novo synthesis of guanine nucleotides.<ref name="entrez"/>

== Clinical significance ==

Defects in the ''IMPDH1'' gene are a cause of [[retinitis pigmentosa]] type 10 (RP10).<ref name="entrez"/><ref name="pmid11875049">{{cite journal |vauthors=Kennan A, Aherne A, Palfi A, Humphries M, McKee A, Stitt A, Simpson DA, Demtroder K, Orntoft T, Ayuso C, Kenna PF, Farrar GJ, Humphries P | title = Identification of an IMPDH1 mutation in autosomal dominant retinitis pigmentosa (RP10) revealed following comparative microarray analysis of transcripts derived from retinas of wild-type and Rho(-/-) mice | journal = Hum. Mol. Genet. | volume = 11 | issue = 5 | pages = 547–57 |date=March 2002 | pmid = 11875049 | doi = 10.1093/hmg/11.5.547| doi-access = }}</ref><ref name="pmid11875050">{{cite journal |vauthors=Bowne SJ, Sullivan LS, Blanton SH, Cepko CL, Blackshaw S, Birch DG, Hughbanks-Wheaton D, Heckenlively JR, Daiger SP | title = Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis pigmentosa | journal = Hum. Mol. Genet. | volume = 11 | issue = 5 | pages = 559–68 |date=March 2002 | pmid = 11875050 | pmc = 2585828 | doi = 10.1093/hmg/11.5.559}}</ref>

== See also ==
* [[IMP dehydrogenase]]

==References==
{{reflist}}

==Further reading==
{{refbegin | 2}}
*{{cite journal |vauthors=Mortimer SE, Xu D, McGrew D, etal |title=IMP dehydrogenase type 1 associates with polyribosomes translating rhodopsin mRNA. |journal=J. Biol. Chem. |volume=283 |issue= 52 |pages= 36354–60 |year= 2008 |pmid= 18974094 |doi= 10.1074/jbc.M806143200 |pmc=2605994 |doi-access=free }}
*{{cite journal |vauthors=Ohmann EL, Burckart GJ, Brooks MM, etal |title=Genetic polymorphisms influence mycophenolate mofetil-related adverse events in pediatric heart transplant patients |journal=The Journal of Heart and Lung Transplantation |volume= 29|issue= 5|pages= 509–516 |year= 2010 |pmid= 20061166 |doi= 10.1016/j.healun.2009.11.602 }}
*{{cite journal |vauthors=Grover S, Fishman GA, Stone EM |title=A novel IMPDH1 mutation (Arg231Pro) in a family with a severe form of autosomal dominant retinitis pigmentosa |journal=Ophthalmology |volume=111 |issue= 10 |pages= 1910–6 |year= 2004 |pmid= 15465556 |doi= 10.1016/j.ophtha.2004.03.039 }}
*{{cite journal |vauthors=Bowne SJ, Liu Q, Sullivan LS, etal |title=Why do mutations in the ubiquitously expressed housekeeping gene IMPDH1 cause retina-specific photoreceptor degeneration? |journal=Invest. Ophthalmol. Vis. Sci. |volume=47 |issue= 9 |pages= 3754–65 |year= 2006 |pmid= 16936083 |doi= 10.1167/iovs.06-0207 |pmc=2581456 }}
*{{cite journal |vauthors=Kimura K, Wakamatsu A, Suzuki Y, etal |title=Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes |journal=Genome Res. |volume=16 |issue= 1 |pages= 55–65 |year= 2006 |pmid= 16344560 |doi= 10.1101/gr.4039406 |pmc=1356129}}
*{{cite journal |vauthors=Schatz P, Ponjavic V, Andréasson S |title=Clinical phenotype in a Swedish family with a mutation in the IMPDH1 gene |journal=Ophthalmic Genet. |volume=26 |issue= 3 |pages= 119–24 |year= 2005 |pmid= 16272056 |doi= 10.1080/13816810500229090 |s2cid=33839722 |display-authors=etal}}
*{{cite journal |vauthors=Wada Y, Tada A, Itabashi T, etal |title=Screening for mutations in the IMPDH1 gene in Japanese patients with autosomal dominant retinitis pigmentosa |journal=Am. J. Ophthalmol. |volume=140 |issue= 1 |pages= 163–5 |year= 2005 |pmid= 16038673 |doi= 10.1016/j.ajo.2005.01.017 }}
*{{cite journal |vauthors=Wang J, Yang JW, Zeevi A, etal |title=IMPDH1 gene polymorphisms and association with acute rejection in renal transplant patients |journal=Clin. Pharmacol. Ther. |volume=83 |issue= 5 |pages= 711–7 |year= 2008 |pmid= 17851563 |doi= 10.1038/sj.clpt.6100347 |s2cid=12718828 }}
*{{cite journal |vauthors=Gandra M, Anandula V, Authiappan V, etal |title=Retinitis pigmentosa: mutation analysis of RHO, PRPF31, RP1, and IMPDH1 genes in patients from India |journal=Mol. Vis. |volume=14 |pages= 1105–13 |year= 2008 |pmid= 18552984 |pmc=2426732 }}
*{{cite journal |vauthors=Bowne SJ, Sullivan LS, Mortimer SE, etal |title=Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and leber congenital amaurosis |journal=Invest. Ophthalmol. Vis. Sci. |volume=47 |issue= 1 |pages= 34–42 |year= 2006 |pmid= 16384941 |doi= 10.1167/iovs.05-0868 |pmc=2581444 }}
*{{cite journal |vauthors=Xu D, Cobb G, Spellicy CJ, etal |title=Retinal isoforms of inosine 5'-monophosphate dehydrogenase type 1 are poor nucleic acid binding proteins |journal=Arch. Biochem. Biophys. |volume=472 |issue= 2 |pages= 100–4 |year= 2008 |pmid= 18295591 |doi= 10.1016/j.abb.2008.02.012 |pmc=2366119 }}
*{{cite journal |vauthors=Gerhard DS, Wagner L, Feingold EA, etal |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 |pmc=528928}}
*{{cite journal |vauthors=Sanquer S, Maison P, Tomkiewicz C, etal |title=Expression of inosine monophosphate dehydrogenase type I and type II after mycophenolate mofetil treatment: a 2-year follow-up in kidney transplantation |journal=Clin. Pharmacol. Ther. |volume=83 |issue= 2 |pages= 328–35 |year= 2008 |pmid= 17713475 |doi= 10.1038/sj.clpt.6100300 |s2cid=44919245 }}
*{{cite journal |vauthors=Ota T, Suzuki Y, Nishikawa T, etal |title=Complete sequencing and characterization of 21,243 full-length human cDNAs |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40–5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 |doi-access= free }}
*{{cite journal |vauthors=Kozma P, Hughbanks-Wheaton DK, Locke KG, etal |title=Phenotypic characterization of a large family with RP10 autosomal-dominant retinitis pigmentosa: an Asp226Asn mutation in the IMPDH1 gene |journal=Am. J. Ophthalmol. |volume=140 |issue= 5 |pages= 858–867 |year= 2005 |pmid= 16214101 |doi= 10.1016/j.ajo.2005.05.027 |pmc=2771559 }}
*{{cite journal |vauthors=Wada Y, Sandberg MA, McGee TL, etal |title=Screen of the IMPDH1 gene among patients with dominant retinitis pigmentosa and clinical features associated with the most common mutation, Asp226Asn |journal=Invest. Ophthalmol. Vis. Sci. |volume=46 |issue= 5 |pages= 1735–41 |year= 2005 |pmid= 15851576 |doi= 10.1167/iovs.04-1197 |doi-access= }}
*{{cite journal |vauthors=Jin P, Fu GK, Wilson AD, etal |title=PCR isolation and cloning of novel splice variant mRNAs from known drug target genes |journal=Genomics |volume=83 |issue= 4 |pages= 566–71 |year= 2004 |pmid= 15028279 |doi= 10.1016/j.ygeno.2003.09.023 }}
*{{cite journal |vauthors=Roberts RL, Gearry RB, Barclay ML, Kennedy MA |title=IMPDH1 promoter mutations in a patient exhibiting azathioprine resistance |journal=Pharmacogenomics J. |volume=7 |issue= 5 |pages= 312–7 |year= 2007 |pmid= 17001353 |doi= 10.1038/sj.tpj.6500421 |doi-access= |s2cid=11257472 }}
*{{cite journal |vauthors=Kudo M, Saito Y, Sasaki T, etal |title=Genetic variations in the HGPRT, ITPA, IMPDH1, IMPDH2, and GMPS genes in Japanese individuals |journal=Drug Metab. Pharmacokinet. |volume=24 |issue= 6 |pages= 557–64 |year= 2009 |pmid= 20045992 |doi= 10.2133/dmpk.24.557}}
{{refend}}

==External links==
* [https://www.ncbi.nlm.nih.gov/books/NBK1417/ GeneReviews/NCBI/NIH/UW entry on Retinitis Pigmentosa Overview]
* {{PDBe-KB2|P20839|Inosine-5'-monophosphate dehydrogenase 1}}

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[[Category:EC 1.1.1]]

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