View source for TAS2R46

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{cs1 config|name-list-style=vanc}}
{{Infobox_gene}}
'''Taste receptor type 2 member 46''' is a [[protein]] that in humans is encoded by the ''TAS2R46'' [[gene]].<ref name="pmid12379855">{{cite journal | vauthors = Bufe B, Hofmann T, Krautwurst D, Raguse JD, Meyerhof W | title = The human TAS2R16 receptor mediates bitter taste in response to beta-glucopyranosides | journal = Nature Genetics | volume = 32 | issue = 3 | pages = 397–401 | date = November 2002 | pmid = 12379855 | doi = 10.1038/ng1014 | s2cid = 20426192 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: TAS2R46 taste receptor, type 2, member 46| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=259292}}</ref>

Taste receptors for bitter substances (T2Rs/TAS2Rs) belong to the family of [[G protein-coupled receptor|G-protein coupled receptors]] and are related to [[GPCR family A|class A]]-like GPCRs. There are 25 known T2Rs in humans responsible for bitter taste perception.<ref>{{cite journal | vauthors = Meyerhof W, Batram C, Kuhn C, Brockhoff A, Chudoba E, Bufe B, Appendino G, Behrens M | display-authors = 6 | title = The molecular receptive ranges of human TAS2R bitter taste receptors | journal = Chemical Senses | volume = 35 | issue = 2 | pages = 157–170 | date = February 2010 | pmid = 20022913 | doi = 10.1093/chemse/bjp092 | doi-access = free }}</ref>

== Gene ==

TAS2R46 gene ('''Taste receptor type 2 member 46''') is a [[protein-coding gene]]. This gene maps to the [[taste receptor]] [[gene cluster]] on chromosome 12.<ref name = "GeneCards_TAS2R46">{{Cite web | title = TAS2R46 | work = GeneCards |url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=TAS2R46 |archive-url= |access-date=}}</ref> hTAS2R46 is a bitter receptor broadly tuned to [[sesquiterpene lactone]]s, related [[clerodane diterpenoid]]s, [[labdane diterpene]]s and more.

== Structure ==

In 2022, the solved structure of Tas2r46<ref name = "BitterDB_TAS2R46">{{cite web | title = hTAS2R46 - Taste receptor type 2 member 46 | work = BitterDB | publisher = The Hebrew University of Jerusalem. | url = https://bitterdb.agri.huji.ac.il/Receptor.php?mode_organism=default&id=46}}</ref> was published in the scientific journal Science<ref name="pmid36108005">{{cite journal | vauthors = Xu W, Wu L, Liu S, Liu X, Cao X, Zhou C, Zhang J, Fu Y, Guo Y, Wu Y, Tan Q, Wang L, Liu J, Jiang L, Fan Z, Pei Y, Yu J, Cheng J, Zhao S, Hao X, Liu ZJ, Hua T | display-authors = 6 | title = Structural basis for strychnine activation of human bitter taste receptor TAS2R46 | journal = Science | volume = 377 | issue = 6612 | pages = 1298–1304 | date = September 2022 | pmid = 36108005 | doi = 10.1126/science.abo1633 | bibcode = 2022Sci...377.1298X | s2cid = 252310278 }}{{Expression of Concern|doi=10.1126/science.adf8367|pmid=36413140|https://retractionwatch.com/2022/11/22/science-paper-on-sense-of-taste-gets-expression-of-concern-as-university-investigates/ ''Retraction Watch''}}</ref> making it the first Tas2r with a solved structure. The structure of Tas2r46 was solved with [[cryo-EM]] and can be downloaded in the [[Protein Data Bank]], under the following names:

[https://www.rcsb.org/structure/7XP6 7xp6]- Cryo-EM structure of a class T GPCR in active state,[https://www.rcsb.org/structure/7XP5 7xp5]- Cryo-EM structure of a class T GPCR in ligand-free state,[https://www.rcsb.org/structure/7XP4 7xp4]- Cryo-EM structure of a class T GPCR in apo state.

There is also a prediction structure available in [[AlphaFold|Alphafold]], named [https://alphafold.ebi.ac.uk/entry/P59540 Taste receptor type 2 member 46] this is a computational prediction and not an experimental structure.

== Tissue distribution ==
TAS2R46 was shown to be expressed in other tissues in the human body apart from the oral cavity including human bone marrow stromal-derived cells (MSC) and their relatives, [[vascular smooth muscle cell]]s (VSMC).<ref name="Lund_2013">{{cite journal | vauthors = Lund TC, Kobs AJ, Kramer A, Nyquist M, Kuroki MT, Osborn J, Lidke DS, Low-Nam ST, Blazar BR, Tolar J | display-authors = 6 | title = Bone marrow stromal and vascular smooth muscle cells have chemosensory capacity via bitter taste receptor expression | journal = PLOS ONE | volume = 8 | issue = 3 | pages = e58945 | date = 2013 | pmid = 23520545 | pmc = 3592821 | doi = 10.1371/journal.pone.0058945 | bibcode = 2013PLoSO...858945L | doi-access = free }}</ref>

== Ligands ==
Up to now, 68 ligands were identified for T2R46 and are summarized in <ref name = "BitterDB_TAS2R46" />

Some of TAS2R46 ligands are approved as drugs;<ref name = "GeneCards_TAS2R46" /> two of the more known ligands of TAS2R46 are [[atropine]] and [[strychnine]].

Strychnine is known as a strong poison that suppresses the nerve system. Strychnine even makes an appearance in the famous [[Agatha Christie]] novel ''[[The Mysterious Affair at Styles]]''.

Atropine injection is used to treat heart rate disorders of various types, and is used in drops to treat [[Lazy Eye (Silversun Pickups song)|lazy eye]] condition.

[[Oligoporin D]] is one of the most potent agonists known for TAS2R46, and thus one of the most bitter substances known.<ref>Schmitz LM, Lang T, Steuer A, Koppelmann L, Di Pizio A, Arnold N, Behrens M. Taste-Guided Isolation of Bitter Compounds from the Mushroom Amaropostia stiptica Activates a Subset of Human Bitter Taste Receptors. ''J Agric Food Chem''. 2025 Feb 26;73(8):4850-4858. {{doi|10.1021/acs.jafc.4c12651}} {{pmid|39945763}}</ref>

== Clinical significance ==
TAS2R46 was associated with [[Inflammatory bowel disease|Inflammatory Bowel Disease]]<ref>{{Cite web |title= Inflammatory Bowel Disease 11 (IBD11) | work = MalaCards-Human disease database | publisher = Weizmann Institute of Science |url=https://www.malacards.org/card/inflammatory_bowel_disease_11}}</ref>

== SNPs ==
Obtained from<ref name = "BitterDB_TAS2R46" />

{| class="wikitable"
|+
|Receptor
|Location
|BW number
|Residue
|MAF
|dbSNP
|-
|TAS2R46
|IC3
|
|L228M
|0.3359
|rs2708380
|}

== Known mutations ==
Known mutations of TAS2R46 include the following:<ref name = "BitterDB_TAS2R46" />
{| class="wikitable"
|Receptor
|Location
|BW number
|Residue
|References
|-
|TAS2R46
|TM2
|2.6
|N65
|<ref name="Sandal_2015">{{cite journal | vauthors = Sandal M, Behrens M, Brockhoff A, Musiani F, Giorgetti A, Carloni P, Meyerhof W | title = Evidence for a Transient Additional Ligand Binding Site in the TAS2R46 Bitter Taste Receptor | journal = Journal of Chemical Theory and Computation | volume = 11 | issue = 9 | pages = 4439–4449 | date = September 2015 | pmid = 26575934 | doi = 10.1021/acs.jctc.5b00472 }}</ref><ref name="Di Pizio_2016">{{cite book | vauthors = Di Pizio A, Levit A, Slutzki M, Behrens M, Karaman R, Niv MY | chapter = Comparing Class a GPCRS to bitter taste receptors | title = G Protein-Coupled Receptors - Signaling, Trafficking and Regulation | series = Methods in Cell Biology | volume = 132 | pages = 401–427 | date = 2016 | pmid = 26928553 | doi = 10.1016/bs.mcb.2015.10.005 | isbn = 978-0-12-803595-5 }}</ref>
|-
|TAS2R46
|TM2
|2.61
|W66
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" /><ref name="Brockhoff_2010">{{cite journal | vauthors = Brockhoff A, Behrens M, Niv MY, Meyerhof W | title = Structural requirements of bitter taste receptor activation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 24 | pages = 11110–11115 | date = June 2010 | pmid = 20534469 | pmc = 2890741 | doi = 10.1073/pnas.0913862107 | bibcode = 2010PNAS..10711110B | doi-access = free }}</ref>
|-
|TAS2R46
|TM2
|2.64
|T69
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" />
|-
|TAS2R46
|TM2
|2.65
|E70
|<ref name="Sandal_2015" /><ref name="Brockhoff_2010" /><ref name="Di Pizio_2016" /><ref name="Fierro_2017" />
|-
|TAS2R46
|EC1
|2.66
|L71
|<ref name="Fierro_2017" /><ref name = "Suku_2017">{{cite journal | vauthors = Suku E, Fierro F, Giorgetti A, Alfonso-Prieto M, Carloni P | title = Multi-scale simulations of membrane proteins: the case of bitter taste receptors. | journal = Journal of Science: Advanced Materials and Devices. | date = March 2017 | volume = 2 | issue = 1 | pages = 15–21 | doi = 10.1016/j.jsamd.2017.03.001 | s2cid = 56035188 | doi-access = free }}</ref>
|-
|TAS2R46
|TM3
|3.26
|I82
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" /><ref name="Fierro_2017" />
|-
|TAS2R46
|TM3
|3.29
|Y85
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" />
|-
|TAS2R46
|TM3
|3.3
|N86
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" />
|-
|TAS2R46
|TM3
|3.32
|W88
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" />
|-
|TAS2R46
|TM3
|3.33
|A89
|<ref name="Sandal_2015" /><ref name="Brockhoff_2010" /><ref name="Di Pizio_2016" />
|-
|TAS2R46
|TM3
|3.36
|N92
|<ref name="Sandal_2015" /><ref name="Brockhoff_2010" /><ref name="Di Pizio_2016" /><ref name="Marchiori_2013">{{cite journal | vauthors = Marchiori A, Capece L, Giorgetti A, Gasparini P, Behrens M, Carloni P, Meyerhof W | title = Coarse-grained/molecular mechanics of the TAS2R38 bitter taste receptor: experimentally-validated detailed structural prediction of agonist binding | journal = PLOS ONE | volume = 8 | issue = 5 | pages = e64675 | date = 2013 | pmid = 23741366 | pmc = 3669430 | doi = 10.1371/journal.pone.0064675 | bibcode = 2013PLoSO...864675M | doi-access = free }}</ref><ref name="Fierro_2017" /><ref name = "Suku_2017" />
|-
|TAS2R46
|TM3
|3.37
|H93
|<ref name="Sandal_2015" /><ref name="Brockhoff_2010" /><ref name="Di Pizio_2016" />
|-
|TAS2R46
|TM3
|3.4
|N96
|<ref name="Sandal_2015" /><ref name="Brockhoff_2010" /><ref name="Di Pizio_2016" />
|-
|TAS2R46
|TM4
|4.6
|I147
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" />
|-
|TAS2R46
|EC2
|4.65
|N150
|<ref name="Fierro_2017" />
|-
|TAS2R46
|EC2
|4.76
|N161
|<ref name="Fierro_2017" />
|-
|TAS2R46
|TM5
|5.38
|S175
|<ref name="Sandal_2015" />
|-
|TAS2R46
|TM5
|5.39
|N176
|<ref name="Sandal_2015" /><ref name="Brockhoff_2010" /><ref name="Di Pizio_2016" /><ref name="Fierro_2017" /><ref name = "Suku_2017" />
|-
|TAS2R46
|TM5
|5.43
|T180
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" />
|-
|TAS2R46
|TM5
|5.47
|N184
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" />
|-
|TAS2R46
|TM6
|6.51
|Y241
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" /><ref name="Fierro_2017" /><ref name = "Suku_2017" />
|-
|TAS2R46
|TM6
|6.52
|F242
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" /><ref name="Marchiori_2013" />
|-
|TAS2R46
|TM6
|6.54
|S244
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" />
|-
|TAS2R46
|TM6
|6.55
|I245
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" />
|-
|TAS2R46
|TM6
|6.58
|S248
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" />
|-
|TAS2R46
|TM6
|6.59
|V249
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" />
|-
|TAS2R46
|EC3
|6.62
|E253
|<ref name="Fierro_2017" />
|-
|TAS2R46
|TM7
|7.35
|E261
|<ref name="Sandal_2015" /><ref name="Di Pizio_2016" /><ref name="Fierro_2017">{{cite journal | vauthors = Fierro F, Suku E, Alfonso-Prieto M, Giorgetti A, Cichon S, Carloni P | title = Agonist Binding to Chemosensory Receptors: A Systematic Bioinformatics Analysis | journal = Frontiers in Molecular Biosciences | volume = 4 | issue =  | pages = 63 | date = 2017 | pmid = 28932739 | pmc = 5592726 | doi = 10.3389/fmolb.2017.00063 | doi-access = free }}</ref>
|-
|TAS2R46
|TM7
|7.39
|E265
|<ref name="Sandal_2015" /><ref name="Brockhoff_2010" /><ref name="Di Pizio_2016" /><ref name="Fierro_2017" />
|-
|TAS2R46
|TM7
|7.42
|A268
|<ref name="Sandal_2015" /><ref name="Brockhoff_2010" /><ref name="Di Pizio_2016" /><ref name="Fierro_2017" />
|-
|TAS2R46
|TM7
|7.43
|F269
|<ref name="Sandal_2015" /><ref name="Brockhoff_2010" /><ref name="Fierro_2017" />
|}

== References ==
{{reflist}}

== Further reading ==
{{refbegin|30em}}
* {{cite journal | vauthors = Margolskee RF | title = Molecular mechanisms of bitter and sweet taste transduction | journal = The Journal of Biological Chemistry | volume = 277 | issue = 1 | pages = 1–4 | date = January 2002 | pmid = 11696554 | doi = 10.1074/jbc.R100054200 | doi-access = free }}
* {{cite journal | vauthors = Montmayeur JP, Matsunami H | title = Receptors for bitter and sweet taste | journal = Current Opinion in Neurobiology | volume = 12 | issue = 4 | pages = 366–371 | date = August 2002 | pmid = 12139982 | doi = 10.1016/S0959-4388(02)00345-8 | s2cid = 37807140 }}
* {{cite journal | vauthors = Zhang Y, Hoon MA, Chandrashekar J, Mueller KL, Cook B, Wu D, Zuker CS, Ryba NJ | display-authors = 6 | title = Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways | journal = Cell | volume = 112 | issue = 3 | pages = 293–301 | date = February 2003 | pmid = 12581520 | doi = 10.1016/S0092-8674(03)00071-0 | s2cid = 718601 | doi-access = free }}
* {{cite journal | vauthors = Conte C, Ebeling M, Marcuz A, Nef P, Andres-Barquin PJ | title = Identification and characterization of human taste receptor genes belonging to the TAS2R family | journal = Cytogenetic and Genome Research | volume = 98 | issue = 1 | pages = 45–53 | year = 2003 | pmid = 12584440 | doi = 10.1159/000068546 | s2cid = 1542970 }}
* {{cite journal | vauthors = Fischer A, Gilad Y, Man O, Pääbo S | title = Evolution of bitter taste receptors in humans and apes | journal = Molecular Biology and Evolution | volume = 22 | issue = 3 | pages = 432–436 | date = March 2005 | pmid = 15496549 | doi = 10.1093/molbev/msi027 | doi-access = free }}
* {{cite journal | vauthors = Go Y, Satta Y, Takenaka O, Takahata N | title = Lineage-specific loss of function of bitter taste receptor genes in humans and nonhuman primates | journal = Genetics | volume = 170 | issue = 1 | pages = 313–326 | date = May 2005 | pmid = 15744053 | pmc = 1449719 | doi = 10.1534/genetics.104.037523 }}
{{refend}}

{{NLM content}}
{{G protein-coupled receptors|g3}}

[[Category:Human taste receptors]]