View source for Arylsulfatase B

{{Short description|Mammalian protein found in Homo sapiens}}
{{More citations needed|auto=yes|date=December 2009}}
{{Use dmy dates|date=April 2020}}
{{Infobox_gene}}

{{Infobox protein
| Name = arylsulfatase B
| caption = [[X-ray crystallography#Biological macromolecular crystallography|Crystallographic structure]] of putative tetrameric arylsulfatase from ''[[Escherichia coli]]''.<ref name="Patskovsky_2010">{{PDB|3ED4}}; {{cite journal | vauthors = Patskovsky Y, Ozyurt S, Gilmore M, Chang S, Bain K, Wasserman S, Koss J, Sauder MJ, Burley SK, Almo SC |title=Crystal structure of putative arylsulfatase from ''Escherichia coli'' | journal=Worldwide Protein Data Bank | year = 2010 | doi=10.2210/pdb3ed4/pdb}}</ref>
| image = Arylsulfatase B.jpg
| width = 
| HGNCid = 714
| Symbol = ARSB
| AltSymbols = 
| EntrezGene = 411
| OMIM = 253200
| RefSeq = NM_000046
| UniProt = P15848
| PDB = 
| ECnumber = 3.1.6.12
| Chromosome = 5
| Arm = p
| Band = 11
| LocusSupplementaryData = -q13
}}
{{Infobox drug
| drug_name         = Galsulfase
| INN               = galsulfase
| type              = <!-- empty -->
| image             = 
| width             = 
| alt               = 
| caption           =

<!-- Clinical data -->
| pronounce         = 
| tradename         = Naglazyme
| Drugs.com         = {{drugs.com|ppa|galsulfase}}
| MedlinePlus       = 
| licence_CA        = <!-- Health Canada may use generic or brand name (generic name preferred) -->
| licence_EU        = <!-- EMA uses INN (or special INN_EMA) -->
| DailyMedID        = Galsulfase
| licence_US        = <!-- FDA may use generic or brand name (generic name preferred) -->
| pregnancy_AU      = B3
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Galsulfase (Naglazyme) Use During Pregnancy | website=Drugs.com | date=11 December 2019 | url=https://www.drugs.com/pregnancy/galsulfase.html | access-date=23 April 2020}}</ref>
| pregnancy_US      = B
| pregnancy_US_comment = <ref name="Drugs.com pregnancy" />
| pregnancy_category= 
| dependency_liability = 
| addiction_liability = 
| routes_of_administration = Intravenous
| class             = 
| ATCvet            = 
| ATC_prefix        = A16
| ATC_suffix        = AB08
| ATC_supplemental  =

<!-- Legal status -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_AU_comment = 
| legal_BR =  <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment = 
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment = 
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment = 
| legal_US = Rx-only
| legal_US_comment = 
| legal_EU = Rx-only
| legal_EU_comment = 
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment = 
| legal_status      = Rx-only

<!-- Pharmacokinetic data -->
| bioavailability   = 
| protein_bound     = 
| metabolism        = 
| metabolites       = 
| onset             = 
| elimination_half-life = 
| duration_of_action = 
| excretion         =

<!-- Identifiers -->
| CAS_number_Ref    = 
| CAS_number        = 552858-79-4
| CAS_supplemental  = 
| PubChem           = 
| PubChemSubstance  = 
| IUPHAR_ligand     = 
| DrugBank_Ref      = 
| DrugBank          = DB01279
| ChemSpiderID_Ref  = 
| ChemSpiderID      = 
| UNII_Ref          = 
| UNII              = 59UA429E5G
| KEGG_Ref          = 
| KEGG              = D06565
| ChEBI_Ref         = 
| ChEBI             = 
| ChEMBL_Ref        = 
| ChEMBL            = 1201822
| NIAID_ChemDB      = 
| PDB_ligand        = 
| synonyms          = Aryplase

<!-- Chemical and physical data -->
| IUPAC_name        = 
| chemical_formula  = 
| C = 2529 | H = 3843 | N = 689 | O = 716 | S = 16
| molecular_weight  = 
| SMILES            = 
| Jmol              = 
| StdInChI          = 
| StdInChI_comment  = 
| StdInChIKey       = 
| density           = 
| density_notes     = 
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| sol_units         = 
| specific_rotation = 
}}

'''Arylsulfatase B''' (N-acetylgalactosamine-4-sulfatase, chondroitinsulfatase, chondroitinase, acetylgalactosamine 4-sulfatase, N-acetylgalactosamine 4-sulfate sulfohydrolase, {{EC number|3.1.6.12}}) is an [[enzyme]] associated with [[mucopolysaccharidosis VI]] (Maroteaux–Lamy syndrome).

Arylsulfatase B is among a group of [[arylsulfatase]] enzymes present in the lysosomes of the [[liver]], [[pancreas]], and [[kidney]]s of animals. The purpose of the enzyme is to hydrolyze sulfates in the body. ARSB does this by breaking down [[glycosaminoglycan]]s (GAGs), which are large sugar molecules in the body. ARSB targets two GAGs in particular: [[dermatan sulfate]] and [[chondroitin sulfate]].<ref name="ARSB">U.S. National Library of Medicine. [http://ghr.nlm.nih.gov/gene/ARSB "ARSB"], Genetics Home Resource, 7 November 2010, Retrieved 22 November 2010</ref>

Over 130 mutations to ARSB have been found, each leading to a deficiency in the body. In most cases, the mutation occurs on a single [[nucleotide]] in the sequence. An arylsulfatase B deficiency can lead to an accumulation of GAGs in lysosomes,<ref name="ARSB"/> which in turn can lead to mucopolysaccharidosis VI.

Used as a pharmaceutical drug, the enzyme is known under the [[International Nonproprietary Name]] '''galsulfase''' and is sold under the brand name '''Naglazyme'''.<ref>{{cite journal |vauthors=Kim KH, Decker C, Burton BK |title=Successful management of difficult infusion-associated reactions in a young patient with mucopolysaccharidosis type VI receiving recombinant human arylsulfatase B (galsulfase [Naglazyme])|journal=Pediatrics|date=March 2008|volume=121|issue=3|pages=e714–7|pmid=18250117|doi=10.1542/peds.2007-0665|s2cid=3298398}}</ref><ref>{{cite journal | vauthors=((World Health Organization)) | year=2005 | title=International nonproprietary names for pharmaceutical substances (INN) : recommended international nonproprietary names (Rec. INN) : list 54 | journal=WHO Drug Information | volume=19 | issue=3 | page=255 | hdl=10665/73503 | hdl-access=free}}</ref><ref name="Naglazyme EPAR">{{cite web | title=Naglazyme EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/naglazyme | access-date=23 April 2020}} {{PD-notice}}</ref> Galsulfase was approved for medical use in the United States in May 2005 and in  European Union in January 2006.<ref>{{cite web | title=Drug Approval Package: Naglazyme (Galsulfase) NDA #125117 | website=U.S. [[Food and Drug Administration]] (FDA) | date=9 September 2005  | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/125117s000_NaglazyneTOC.cfm | access-date=23 April 2020}}</ref><ref name="Naglazyme EPAR" /> Galsulfase is indicated for long-term enzyme-replacement therapy in people with a confirmed diagnosis of mucopolysaccharidosis VI (MPS VI; N-acetylgalactosamine-4-sulfatase deficiency; Maroteaux-Lamy syndrome).<ref name="Naglazyme EPAR" />

[[File:Arylsulfatase B hydropathy plot.png|thumb|left|Kyte-Doolittle hydropathy plot: enlarge for better viewing]]

== Structure ==

The primary structure of ''[[Escherichia coli]]''  arylsulfatase B contains a primary sequence of 502 amino acids. Its secondary structure is quite complex, containing numerous [[Alpha helix|alpha helices]] (20 total containing 138 residues) and [[beta sheet]]s (21 strands total containing 87 residues).<ref name="Patskovsky_2010"/>  The functional enzyme is believed to be a homo [[tetramer]]. Due to the complexity of arylsulfatase B's secondary structure, many hydrophobic and hydrophilic regions are present, as demonstrated by the Kyte-Doolittle hydropathy plot:

== Medical uses ==
Galsulfase is used to treat adults and children who have mucopolysaccharidosis VI (MPS VI or Maroteaux-Lamy syndrome).<ref name="Naglazyme EPAR" /> This disease is caused by the lack of an enzyme called N-acetylgalactosamine 4-sulfatase, which is needed to break down substances in the body called glycosaminoglycans (GAGs).<ref name="Naglazyme EPAR" /> If the enzyme is not present, GAGs cannot be broken down and they build up in the cells.<ref name="Naglazyme EPAR" /> This causes the signs of the disease, the most noticeable being a short body, a large head and difficulty moving about.<ref name="Naglazyme EPAR" /> The disease is usually diagnosed in infants between one and five years of age.<ref name="Naglazyme EPAR" /> Galsulfase has been shown to improve walking and stair-climbing capacity.<ref name="Naglazyme FDA label">{{cite web | title=Naglazyme- galsulfase solution | website=DailyMed | date=14 April 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=59341250-deac-ed71-3823-a4f5d64dbd77 | access-date=23 April 2020}}</ref>

The most common adverse reactions (≥10%) are: rash, pain, urticaria, pyrexia, pruritus, chills, headache, nausea, vomiting, abdominal pain and dyspnea.<ref name="Naglazyme FDA label" /> The most common adverse reactions requiring interventions are infusion-related reactions.<ref name="Naglazyme FDA label" />

Galsulfase (N-acetylgalactosamine-4-sulfatase, recombinant human) was granted orphan drug designation by both the European Commission and the U.S. [[Food and Drug Administration]] (FDA).<ref>{{cite web | title=EU/3/01/025 | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu301025 | access-date=23 April 2020}}</ref><ref>{{cite web | title=Naglazyme Orphan Drug Designation and Approval | website=accessdata.fda.gov | date=24 December 1999 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=119898 | archive-url=https://web.archive.org/web/20241201164952/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=119898 | url-status=dead | archive-date=1 December 2024 | access-date=23 April 2020}}</ref>

== Role in cystic fibrosis ==
Expression and activity of ARSB were found to be related to the function of [[cystic fibrosis transmembrane conductance regulator]] (CFTR), the membrane channel deficient in [[cystic fibrosis]]. Measurements in cystic fibrosis cell line IB3 and its derivative cell line C38, which has a functional CFTR, showed increased ARSB activity and expression in the C38 line.<ref>{{cite journal | vauthors = Bhattacharyya S, Look D, Tobacman JK | title = Increased arylsulfatase B activity in cystic fibrosis cells following correction of CFTR | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 380 | issue = 1–2 | pages = 122–7 | year = 2007 | pmid = 17324393 | doi = 10.1016/j.cca.2007.01.021 }}</ref> CFTR potentiator VRT-532 increased ARSB expression and activity in cystic fibrosis cells to the level in the normal [[Respiratory epithelium|bronchial epithelial cells]].<ref name="pmid26656789">{{cite journal | vauthors = Bhattacharyya S, Feferman L, Tobacman JK | title = Effect of CFTR modifiers on arylsulfatase B activity in cystic fibrosis and normal human bronchial epithelial cells | journal = Pulmonary Pharmacology & Therapeutics | volume = 36 | pages = 22–30 | year = 2016 | pmid = 26656789 | doi = 10.1016/j.pupt.2015.11.005 }}</ref>

== Role in malignancy ==
ARSB has been studied in a variety of cancers. Cultured normal mammary epithelial and [[myoepithelial cells]] had significantly higher ARSB activity than cultured malignant mammary cells.<ref name="pmid17064891">{{cite journal | vauthors = Bhattacharyya S, Tobacman JK | title = Steroid sulfatase, arylsulfatases A and B, galactose-6-sulfatase, and iduronate sulfatase in mammary cells and effects of sulfated and non-sulfated estrogens on sulfatase activity | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 103 | issue = 1 | pages = 20–34 | year = 2007 | pmid = 17064891 | doi = 10.1016/j.jsbmb.2006.08.002 | s2cid = 10970204 }}</ref> Immunohistochemistry  in the colon showed decreased membrane ARSB staining in [[colon cancer]] compared to normal colon, as well as in higher grade malignancies.<ref name="colon">{{cite journal | vauthors = Prabhu SV, Bhattacharyya S, Guzman-Hartman G, Macias V, Kajdacsy-Balla A, Tobacman JK | title = Extra-lysosomal localization of arylsulfatase B in human colonic epithelium | journal = The Journal of Histochemistry and Cytochemistry | volume = 59 | issue = 3 | pages = 328–35 | year = 2011 | pmid = 21378286 | pmc = 3201152 | doi = 10.1369/0022155410395511 }}</ref> ARSB activity was lower in malignant than normal prostate tissue, and immunostaining of prostate tissue microarrays showed not only decreasing ARSB staining in [[prostate cancer]] tissue of a higher [[Gleason score]], but also lower staining in patients with recurrent compared to non-recurrent cancer. ARSB staining was a greater predictor of recurrence than [[Prostate-specific antigen]] (PSA) test, indicating possible future role of ARSB as a prognostic biomarker of prostate cancer.<ref name = "biomarker">{{cite journal | vauthors = Feferman L, Bhattacharyya S, Deaton R, Gann P, Guzman G, Kajdacsy-Balla A, Tobacman JK | title = Arylsulfatase B (N-acetylgalactosamine-4-sulfatase): potential role as a biomarker in prostate cancer | journal = Prostate Cancer and Prostatic Diseases | volume = 16 | issue = 3 | pages = 277–84 | year = 2013 | pmid = 23835622 | pmc = 3763935 | doi = 10.1038/pcan.2013.18 }}</ref> Further evidence of ARSB as a tumor suppressor was determined by molecular studies in cell cultures where ARSB was silenced by [[siRNA]]. The studies showed that decrease of ARSB leads to increase in free [[galectin-3]], which attaches more strongly to less sulfated chondroitin 4-sulfate. Galectin-3 then acts on transcription factors [[AP-1 (transcription factor)|AP-1]] to increase expression of chondroitin sulfate [[proteoglycan]] [[versican]] and [[Sp1 transcription factor|SP-1]] to increase expression of [[WNT9A]].<ref name="pmid24240681">{{cite journal | vauthors = Bhattacharyya S, Feferman L, Tobacman JK | title = Arylsulfatase B regulates versican expression by galectin-3 and AP-1 mediated transcriptional effects | journal = Oncogene | volume = 33 | issue = 47 | pages = 5467–76 | year = 2014 | pmid = 24240681 | pmc = 4024465 | doi = 10.1038/onc.2013.483 }}</ref><ref name="pmid24778176">{{cite journal | vauthors = Bhattacharyya S, Feferman L, Tobacman JK | title = Increased expression of colonic Wnt9A through Sp1-mediated transcriptional effects involving arylsulfatase B, chondroitin 4-sulfate, and galectin-3 | journal = The Journal of Biological Chemistry | volume = 289 | issue = 25 | pages = 17564–75 | year = 2014 | pmid = 24778176 | pmc = 4067192 | doi = 10.1074/jbc.M114.561589 | doi-access = free }}</ref> Another mechanism by which reduced ARSB is associated with carcinogenesis is through increased binding of [[PTPN11|SHP2]] to more sulfated chondroitin 4-sulfate, which leads to increased phosphorylation of [[p38 mitogen-activated protein kinases|p38]] and [[Microphthalmia-associated transcription factor|MITF]] with subsequently increased expression of [[GPNMB]].<ref name="pmid27078017">{{cite journal | vauthors = Bhattacharyya S, Feferman L, Tobacman JK | title = Inhibition of Phosphatase Activity Follows Decline in Sulfatase Activity and Leads to Transcriptional Effects through Sustained Phosphorylation of Transcription Factor MITF | journal = PLOS ONE | volume = 11 | issue = 4 | pages = e0153463 | year = 2016 | pmid = 27078017 | pmc = 4831796 | doi = 10.1371/journal.pone.0153463 | bibcode = 2016PLoSO..1153463B | doi-access = free }}</ref>

== Role in metabolism ==
Reduced sulfate availability due to impaired activity of ARSB has been linked to increased [[Aerobic respiration|aerobic]] [[glycolysis]], as shown by an increase in [[Nicotinamide adenine dinucleotide|NADH]] and [[Nicotinamide adenine dinucleotide phosphate|NADPH]], reduced oxygen consumption, increased extracellular acidification and [[Serum (blood)|serum]] [[Lactic acid|lactate]], and a decline in [[Mitochondrion|mitochondrial]] [[membrane potential]] in ARSB-silenced cells and ARSB-[[null mouse]] tissues.<ref name="pmid27605497">{{cite journal | vauthors = Bhattacharyya S, Feferman L, Tobacman JK | title = Restriction of Aerobic Metabolism by Acquired or Innate Arylsulfatase B Deficiency: A New Approach to the Warburg Effect | journal = Scientific Reports | volume = 6 | pages = 32885 | year = 2016 | pmid = 27605497 | pmc = 5015117 | doi = 10.1038/srep32885 | bibcode = 2016NatSR...632885B }}</ref>

== Extra-lysosomal localization ==
Although primarily a lysosomal enzyme, ARSB was also found to localize at the cell membrane of [[hepatocytes]], [[sinusoidal endothelial cells]], and [[Kupffer cells]] in the liver, as well as in the apical membranes of normal and malignant colonic and prostatic [[epithelial cells]], by [[immunohistochemistry]] and [[immunofluorescence]] studies. Membrane immunostaining in the colon and prostate was lower in malignant than in normal tissue and also was lower in higher grade malignancies.<ref name = "colon"/><ref name = "biomarker"/><ref name="pmid19536613">{{cite journal | vauthors = Mitsunaga-Nakatsubo K, Kusunoki S, Kawakami H, Akasaka K, Akimoto Y | title = Cell-surface arylsulfatase A and B on sinusoidal endothelial cells, hepatocytes, and Kupffer cells in mammalian livers | journal = Medical Molecular Morphology | volume = 42 | issue = 2 | pages = 63–9 | year = 2009 | pmid = 19536613 | doi = 10.1007/s00795-009-0447-x | s2cid = 7523889 }}</ref> ARSB activity assay in the membrane and cytosol fractions of cultured bronchial epithelial cells showed that the activity was several-fold greater in the membrane fraction.<ref name="pmid19346317">{{cite journal | vauthors = Bhattacharyya S, Solakyildirim K, Zhang Z, Chen ML, Linhardt RJ, Tobacman JK | title = Cell-bound IL-8 increases in bronchial epithelial cells after arylsulfatase B silencing due to sequestration with chondroitin-4-sulfate | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 42 | issue = 1 | pages = 51–61 | year = 2010 | pmid = 19346317 | doi = 10.1165/rcmb.2008-0482OC | citeseerx = 10.1.1.651.8409 }}</ref>

== See also ==
* [[Aryl]]
* [[Sulfatase]]

== References ==
{{Reflist}}

== Further reading ==
* {{cite journal |vauthors=Brunelli MJ, Atallah ÁN, da Silva EM |title=Enzyme replacement therapy with galsulfase for mucopolysaccharidosis type VI |journal=Cochrane Database Syst Rev |volume=2021 |pages=CD009806 |date=September 2021 |issue=9 |pmid=34533215 |doi=10.1002/14651858.CD009806.pub3 |pmc=8447860 |doi-access=free}}
* {{cite book | chapter=Galsulfase (Naglazyme) | title=Common Drug Review | url=https://www.ncbi.nlm.nih.gov/books/NBK195629/ | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK409829/ | pmid=28121110 | location=Ottawa (ON) | publisher=Canadian Agency for Drugs and Technologies in Health (CADTH) | date=November 2016 }}
* {{cite journal |vauthors=Ferreira CR, Gahl WA |title=Lysosomal storage diseases |journal=Transl Sci Rare Dis |volume=2 |issue=1–2 |pages=1–71 |date=May 2017 |pmid=29152458 |pmc=5685203 |doi=10.3233/TRD-160005 }}

== External links ==
* [http://medical-dictionary.thefreedictionary.com/arylsulfatase Medical Dictionary], Arylsulfatase B function.
* [http://www.rcsb.org/pdb/explore/explore.do?structureId=3ED4 Protein Data Base (PDB)], Arylsulfatase structure.
* [http://ghr.nlm.nih.gov/gene/ARSB Genetics Home Reference], Arylsulfatase B function.
* {{PDBe-KB2|P15848|Arylsulfatase B}}
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/galsulfase | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Galsulfase }}
* {{MeSH name|Galsulfase}}

{{Esterases}}
{{Glycosaminoglycan metabolism enzymes}}
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[[Category:Orphan drugs]]