Arylsulfatase B

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

ARSB
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1FSU
Identifiers
Aliases	ARSB, arylsulfatase B, ASB, G4S, MPS6
External IDs	OMIM: 611542 MGI: 88075 HomoloGene: 73870 GeneCards: ARSB
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q14.1 Start 78,777,209 bp[1] End 78,986,087 bp[1]
Gene location (Mouse) Chr. Chromosome 13 (mouse)[2] Band 13 C3|13 47.88 cM Start 93,771,630 bp[2] End 93,943,016 bp[2]
Gene ontology Molecular function • metal ion binding • arylsulfatase activity • catalytic activity • N-acetylgalactosamine-4-sulfatase activity • sulfuric ester hydrolase activity • hydrolase activity Cellular component • rough endoplasmic reticulum • Golgi apparatus • endoplasmic reticulum lumen • cell surface • lysosomal lumen • mitochondrion • lysosome • extracellular exosome • extracellular region • azurophil granule lumen • ficolin-1-rich granule lumen Biological process • glycosphingolipid metabolic process • response to nutrient • post-translational modification • response to estrogen • autophagy • regulation of epithelial cell migration • central nervous system development • colon epithelial cell migration • positive regulation of neuron projection development • response to pH • chondroitin sulfate catabolic process • lysosomal transport • metabolism • response to methylmercury • lysosome organization • neutrophil degranulation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	411	11881
Ensembl	ENSG00000113273	ENSMUSG00000042082
UniProt	P15848	P50429
RefSeq (mRNA)	NM_000046 NM_198709	NM_009712
RefSeq (protein)	NP_000037 NP_942002	NP_033842
Location (UCSC)	Chr 5: 78.78 – 78.99 Mb	Chr 13: 93.77 – 93.94 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

arylsulfatase B
Crystallographic structure of putative tetrameric arylsulfatase from Escherichia coli.[5]
Identifiers
Symbol	ARSB
NCBI gene	411
HGNC	714
OMIM	253200
RefSeq	NM_000046
UniProt	P15848
Other data
EC number	3.1.6.12
Locus	Chr. 5 p11-q13

Galsulfase
INN: galsulfase

Clinical data
Trade names	Naglazyme
Other names	Aryplase
AHFS/Drugs.com	Professional Drug Facts
License data	US DailyMed: Galsulfase
Pregnancy category	AU: B3 [6] US: B (No risk in non-human studies) [6]
Routes of administration	Intravenous
ATC code	A16AB08 (WHO)
Legal status
Legal status	US: ℞-only In general: ℞ (Prescription only)
Identifiers
CAS Number	552858-79-4
DrugBank	DB01279
UNII	59UA429E5G
KEGG	D06565
ChEMBL	ChEMBL1201822
Chemical and physical data
Formula	C2529H3843N689O716S16
Molar mass	55868.63 g·mol^−1

Arylsulfatase B is among a group of arylsulfatase enzymes present in the lysosomes of the liver, pancreas, and kidneys of animals. The purpose of the enzyme is to hydrolyze sulfates in the body. ARSB does this by breaking down glycosaminoglycans (GAGs), which are large sugar molecules in the body. ARSB targets two GAGs in particular: dermatan sulfate and chondroitin sulfate.[7]

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,[7] 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.[8][9][10] Galsulfase was approved for medical use in the United States in May 2005 and in European Union in January 2006.[11][10] 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).[10]

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 helices (20 total containing 138 residues) and beta sheets (21 strands total containing 87 residues).[5] 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:

Kyte-Doolittle hydropathy plot: enlarge for better viewing

Medical uses

Galsulfase is used to treat adults and children who have mucopolysaccharidosis VI (MPS VI or Maroteaux-Lamy syndrome).[10] 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).[10] If the enzyme is not present, GAGs cannot be broken down and they build up in the cells.[10] This causes the signs of the disease, the most noticeable being a short body, a large head and difficulty moving about.[10] The disease is usually diagnosed in infants between one and five years of age.[10] Galsulfase has been shown to improve walking and stair-climbing capacity.[12]

The most common adverse reactions (≥10%) are: rash, pain, urticaria, pyrexia, pruritus, chills, headache, nausea, vomiting, abdominal pain and dyspnea.[12] The most common adverse reactions requiring interventions are infusion-related reactions.[12]

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).[13][14]

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.[15] CFTR potentiator VRT-532 increased ARSB expression and activity in cystic fibrosis cells to the level in the normal bronchial epithelial cells.[16]

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.[17] Immunohistochemistry in the colon showed decreased membrane ARSB staining in colon cancer compared to normal colon, as well as in higher grade malignancies.[18] 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.[19] 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 to increase expression of chondroitin sulfate proteoglycan versican and SP-1 to increase expression of WNT9A.[20][21] Another mechanism by which reduced ARSB is associated with carcinogenesis is through increased binding of SHP2 to more sulfated chondroitin 4-sulfate, which leads to increased phosphorylation of p38 and MITF with subsequently increased expression of GPNMB.[22] In melanoma cells and normal melanocytes, ARSB silencing increased invasiveness and expression of CSPG4 and MMP2, known markers of melanoma progression. CSPG4 expression was mediated by reduced binding of galectin-3 to C4S, while MMP2 expression was mediated by increased binding of SHP2 to C4S.[23]

Role in metabolism

Reduced sulfate availability due to impaired activity of ARSB has been linked to increased aerobic glycolysis, as shown by an increase in NADH and NADPH, reduced oxygen consumption, increased extracellular acidification and serum lactate, and a decline in mitochondrial membrane potential in ARSB-silenced cells and ARSB-null mouse tissues.[24]

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.[18][19][25] 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.[26]

See also

• Sulfatase
• Aryl

References

1. GRCh38: Ensembl release 89: ENSG00000113273 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000042082 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. PDB: 3ED4​; Patskovsky Y, Ozyurt S, Gilmore M, Chang S, Bain K, Wasserman S, Koss J, Sauder MJ, Burley SK, Almo SC (2010). "Crystal structure of putative arylsulfatase from Escherichia coli". To be Published. doi:10.2210/pdb3ed4/pdb.
6. "Galsulfase (Naglazyme) Use During Pregnancy". Drugs.com. 11 December 2019. Retrieved 23 April 2020.
7. U.S. National Library of Medicine. "ARSB", Genetics Home Resource, November 7, 2010, Retrieved November 22, 2010
8. Kim KH, Decker C, Burton BK (March 2008). "Successful management of difficult infusion-associated reactions in a young patient with mucopolysaccharidosis type VI receiving recombinant human arylsulfatase B (galsulfase [Naglazyme])". Pediatrics. 121 (3): e714–7. doi:10.1542/peds.2007-0665. PMID 18250117.
9. World Health Organization (2005). "International nonproprietary names for pharmaceutical substances (INN) : recommended international nonproprietary names (Rec. INN) : list 54". WHO Drug Information. 19 (3): 255. hdl:10665/73503.
10. "Naglazyme EPAR". European Medicines Agency (EMA). Retrieved 23 April 2020. This article incorporates text from this source, which is in the public domain.
11. "Drug Approval Package: Naglazyme (Galsulfase) NDA #125117". U.S. Food and Drug Administration (FDA). 9 September 2005. Retrieved 23 April 2020.
12. "Naglazyme- galsulfase solution". DailyMed. 14 April 2020. Retrieved 23 April 2020.
13. "EU/3/01/025". European Medicines Agency (EMA). Retrieved 23 April 2020.
14. "Naglazyme Orphan Drug Designation and Approval". accessdata.fda.gov. 24 December 1999. Retrieved 23 April 2020.
15. Bhattacharyya S, Look D, Tobacman JK (2007). "Increased arylsulfatase B activity in cystic fibrosis cells following correction of CFTR". Clinica Chimica Acta; International Journal of Clinical Chemistry. 380 (1–2): 122–7. doi:10.1016/j.cca.2007.01.021. PMID 17324393.
16. Bhattacharyya S, Feferman L, Tobacman JK (2016). "Effect of CFTR modifiers on arylsulfatase B activity in cystic fibrosis and normal human bronchial epithelial cells". Pulmonary Pharmacology & Therapeutics. 36: 22–30. doi:10.1016/j.pupt.2015.11.005. PMID 26656789.
17. Bhattacharyya S, Tobacman JK (2007). "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". The Journal of Steroid Biochemistry and Molecular Biology. 103 (1): 20–34. doi:10.1016/j.jsbmb.2006.08.002. PMID 17064891.
18. Prabhu SV, Bhattacharyya S, Guzman-Hartman G, Macias V, Kajdacsy-Balla A, Tobacman JK (2011). "Extra-lysosomal localization of arylsulfatase B in human colonic epithelium". The Journal of Histochemistry and Cytochemistry. 59 (3): 328–35. doi:10.1369/0022155410395511. PMC 3201152. PMID 21378286.
19. Feferman L, Bhattacharyya S, Deaton R, Gann P, Guzman G, Kajdacsy-Balla A, Tobacman JK (2013). "Arylsulfatase B (N-acetylgalactosamine-4-sulfatase): potential role as a biomarker in prostate cancer". Prostate Cancer and Prostatic Diseases. 16 (3): 277–84. doi:10.1038/pcan.2013.18. PMC 3763935. PMID 23835622.
20. Bhattacharyya S, Feferman L, Tobacman JK (2014). "Arylsulfatase B regulates versican expression by galectin-3 and AP-1 mediated transcriptional effects". Oncogene. 33 (47): 5467–76. doi:10.1038/onc.2013.483. PMC 4024465. PMID 24240681.
21. Bhattacharyya S, Feferman L, Tobacman JK (2014). "Increased expression of colonic Wnt9A through Sp1-mediated transcriptional effects involving arylsulfatase B, chondroitin 4-sulfate, and galectin-3". The Journal of Biological Chemistry. 289 (25): 17564–75. doi:10.1074/jbc.M114.561589. PMC 4067192. PMID 24778176.
22. Bhattacharyya S, Feferman L, Tobacman JK (2016). "Inhibition of Phosphatase Activity Follows Decline in Sulfatase Activity and Leads to Transcriptional Effects through Sustained Phosphorylation of Transcription Factor MITF". PLOS ONE. 11 (4): e0153463. doi:10.1371/journal.pone.0153463. PMC 4831796. PMID 27078017.
23. Sumit Bhattacharyya, Leo Feferman, Kaoru Terai, Arkadiusz Z. Dudek, Joanne K. Tobacman. Decline in arylsulfatase B leads to increased invasiveness of melanoma cells. Oncotarget. December 1, 2016.
24. Bhattacharyya S, Feferman L, Tobacman JK (2016). "Restriction of Aerobic Metabolism by Acquired or Innate Arylsulfatase B Deficiency: A New Approach to the Warburg Effect". Scientific Reports. 6: 32885. doi:10.1038/srep32885. PMC 5015117. PMID 27605497.
25. Mitsunaga-Nakatsubo K, Kusunoki S, Kawakami H, Akasaka K, Akimoto Y (2009). "Cell-surface arylsulfatase A and B on sinusoidal endothelial cells, hepatocytes, and Kupffer cells in mammalian livers". Medical Molecular Morphology. 42 (2): 63–9. doi:10.1007/s00795-009-0447-x. PMID 19536613.
26. Bhattacharyya S, Solakyildirim K, Zhang Z, Chen ML, Linhardt RJ, Tobacman JK (2010). "Cell-bound IL-8 increases in bronchial epithelial cells after arylsulfatase B silencing due to sequestration with chondroitin-4-sulfate". American Journal of Respiratory Cell and Molecular Biology. 42 (1): 51–61. CiteSeerX 10.1.1.651.8409. doi:10.1165/rcmb.2008-0482OC. PMID 19346317.

Further reading

• Brunelli MJ, Atallah ÁN, da Silva EM (March 2016). "Enzyme replacement therapy with galsulfase for mucopolysaccharidosis type VI". Cochrane Database Syst Rev. 3: CD009806. doi:10.1002/14651858.CD009806.pub2. PMID 26943923.
• "Galsulfase (Naglazyme)". Common Drug Review. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health (CADTH). November 2016. PMID 28121110.
• Ferreira CR, Gahl WA (May 2017). "Lysosomal storage diseases". Transl Sci Rare Dis. 2 (1–2): 1–71. doi:10.3233/TRD-160005. PMC 5685203. PMID 29152458.

External links

• Medical Dictionary, Arylsulfatase B function.
• Protein Data Base (PDB), Arylsulfatase structure.
• Genetics Home Reference, Arylsulfatase B function.
• Overview of all the structural information available in the PDB for UniProt: P15848 (Arylsulfatase B) at the PDBe-KB.
• "Galsulfase". Drug Information Portal. U.S. National Library of Medicine.
• Galsulfase at the US National Library of Medicine Medical Subject Headings (MeSH)