Steroid sulfatase

Steroid sulfatase (STS), or steryl-sulfatase (EC 3.1.6.2), formerly known as arylsulfatase C, is a sulfatase enzyme involved in the metabolism of steroids. It is encoded by the STS gene.[3]

STS
Available structures
PDBHuman UniProt search: PDBe RCSB
Identifiers
AliasesSTS, ARSC, ARSC2, ARSC1, ASC, ES, SSDD, XLI, Steroid sulfatase (microsomal), isozyme S, steroid sulfatase
External IDsOMIM: 300747 HomoloGene: 47918 GeneCards: STS
Orthologs
SpeciesHumanMouse
Entrez

412

n/a

Ensembl

ENSG00000101846

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UniProt

P08842

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RefSeq (mRNA)

n/a

RefSeq (protein)

n/a

Location (UCSC)Chr X: 7.15 – 7.8 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human
Steryl-sulfatase
Identifiers
EC no.3.1.6.2
CAS no.9025-62-1
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Search
PMCarticles
PubMedarticles
NCBIproteins

Reactions

This enzyme catalyses the following chemical reaction

3β-hydroxyandrost-5-en-17-one 3-sulfate + H2O 3β-hydroxyandrost-5-en-17-one + sulfate

Also acts on some related steryl sulfates.

Function

The protein encoded by this gene catalyzes the conversion of sulfated steroid precursors to the free steroid. This includes DHEA sulfate, estrone sulfate, pregnenolone sulfate, and cholesterol sulfate, all to their unconjugated forms (DHEA, estrone, pregnenolone, and cholesterol, respectively).[4][5] The encoded protein is found in the endoplasmic reticulum, where it is present as a homodimer.[3]

Distribution of STS and ESTTooltip estrogen sulfotransferase activities for interconversion of estrone (E1) and estrone sulfate (E1S) in adult human tissues.[6]

Clinical significance

A congenital deficiency in the enzyme is associated with X-linked ichthyosis, a scaly-skin disease affecting roughly 1 in every 2,000 to 6,000 males.[7][8] The excessive skin scaling and hyperkeratosis is caused by a lack of breakdown and thus accumulation of cholesterol sulfate, a steroid that stabilizes cell membranes and adds cohesion, in the outer layers of the skin.[4]

Genetic deletions including STS are associated with an increased risk of developmental and mood disorders (and associated traits), and of atrial fibrillation or atrial flutter in males.[9] Both steroid sulfatase deficiency and common genetic risk variants within STS may confer increased atrial fibrillation risk.[10] Blood-clotting abnormalities may occur more frequently in males with XLI and female carriers.[11] Knockdown of STS gene expression in human skin cell cultures affects pathways associated with skin function, brain and heart development, and blood-clotting that may be relevant for explaining the skin condition and increased likelihood of ADHD/autism, cardiac arrhythmias and disorders of hemostasis in XLI.[12]

Steroid sulfates like DHEA sulfate and estrone sulfate serve as large biologically inert reservoirs for conversion into androgens and estrogens, respectively, and hence are of significance for androgen- and estrogen-dependent conditions like prostate cancer, breast cancer, endometriosis, and others. A number of clinical trials have been performed with inhibitors of the enzyme that have demonstrated clinical benefit, particularly in oncology and so far up to Phase II.[13] The non-steroidal drug Irosustat has been the most studied to date.

Inhibitors

Inhibitors of STS include irosustat, estrone sulfamate (EMATE), estradiol sulfamate (E2MATE), and danazol.[14][15] The most potent inhibitors are based around the aryl sulfamate pharmacophore[16] and it is thought that such compounds irreversibly modify the active site formylglycine residue of steroid sulfatase.[13]

Names

Steryl-sulfatase is also known as arylsulfatase, steroid sulfatase, sterol sulfatase, dehydroepiandrosterone sulfate sulfatase, arylsulfatase C, steroid 3-sulfatase, steroid sulfate sulfohydrolase, dehydroepiandrosterone sulfatase, pregnenolone sulfatase, phenolic steroid sulfatase, 3-beta-hydroxysteroid sulfate sulfatase, as well as by its systematic name steryl-sulfate sulfohydrolase.[17][18][19]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000101846 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Entrez Gene: STS steroid sulfatase (microsomal), arylsulfatase C, isozyme S".
  4. Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA (October 2015). "The Regulation of Steroid Action by Sulfation and Desulfation". Endocrine Reviews. 36 (5): 526–63. doi:10.1210/er.2015-1036. PMC 4591525. PMID 26213785.
  5. Rižner TL (2016). "The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases". Frontiers in Pharmacology. 7: 30. doi:10.3389/fphar.2016.00030. PMC 4757672. PMID 26924986.
  6. Miki Y, Nakata T, Suzuki T, Darnel AD, Moriya T, Kaneko C, et al. (December 2002). "Systemic distribution of steroid sulfatase and estrogen sulfotransferase in human adult and fetal tissues". The Journal of Clinical Endocrinology and Metabolism. 87 (12): 5760–8. doi:10.1210/jc.2002-020670. PMID 12466383.
  7. Alperin ES, Shapiro LJ (August 1997). "Characterization of point mutations in patients with X-linked ichthyosis. Effects on the structure and function of the steroid sulfatase protein". The Journal of Biological Chemistry. 272 (33): 20756–63. doi:10.1074/jbc.272.33.20756. PMID 9252398.
  8. Ghosh D (December 2004). "Mutations in X-linked ichthyosis disrupt the active site structure of estrone/DHEA sulfatase". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1739 (1): 1–4. doi:10.1016/j.bbadis.2004.09.003. PMID 15607112.
  9. Brcic L, Underwood JF, Kendall KM, Caseras X, Kirov G, Davies W (Mar 2020). "Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank". Journal of Medical Genetics. 57 (10): 692–698. doi:10.1136/jmedgenet-2019-106676. PMC 7525778. PMID 32139392.
  10. Wren G, Baker E, Underwood J, Humby T, Thompson A, Kirov G, Escott-Price V, Davies W (November 2022). "Characterising heart rhythm abnormalities associated with Xp22.31 deletion". Journal of Medical Genetics. 60 (7): 636–643. doi:10.1136/jmg-2022-108862. PMC 10359567. PMID 36379544.
  11. Brcic L, Wren GH, Underwood JFG, Kirov G, Davies W (2022) Comorbid medical issues in X-linked ichthyosis. JID Innovations 2(3):100109 PMID 35330591 doi:10.1016/j.xjidi.2022.100109 URL: https://www.jidinnovations.org/article/S2667-0267(22)00016-9/fulltext
  12. McGeoghan F, Camera E, Maiellaro M, Menon M, Huang M, Dewan P, Ziaj S, Caley MP, Donaldson M, Enright AJ, O'Toole EA (2023) RNA sequencing and lipidomics uncovers novel pathomechanisms in recessive X-linked ichthyosis Frontiers in Molecular Biosciences 10:1176802 PMID 37363400 doi:10.3389/fmolb.2023.1176802 URL:https://www.frontiersin.org/articles/10.3389/fmolb.2023.1176802/full
  13. Potter BV (August 2018). "SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects". Journal of Molecular Endocrinology. 61 (2): T233–T252. doi:10.1530/JME-18-0045. PMID 29618488.
  14. Thomas MP, Potter BV (September 2015). "Estrogen O-sulfamates and their analogues: Clinical steroid sulfatase inhibitors with broad potential". The Journal of Steroid Biochemistry and Molecular Biology. 153: 160–9. doi:10.1016/j.jsbmb.2015.03.012. PMID 25843211. S2CID 24116740.
  15. Carlström K, Döberl A, Pousette A, Rannevik G, Wilking N (1984). "Inhibition of steroid sulfatase activity by danazol". Acta Obstetricia et Gynecologica Scandinavica Supplement. 123: 107–11. doi:10.3109/00016348409156994. PMID 6238495. S2CID 45817485.
  16. Thomas MP, Potter BV (October 2015). "Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women's Health". Journal of Medicinal Chemistry. 58 (19): 7634–58. doi:10.1021/acs.jmedchem.5b00386. PMC 5159624. PMID 25992880.
  17. Roy AB (October 1954). "The steroid sulphatase of Patella vulgata". Biochimica et Biophysica Acta. 15 (2): 300–1. doi:10.1016/0006-3002(54)90078-5. PMC 1274509. PMID 13208702.
  18. Roy AB (1960). "The Synthesis and Hydrolysis of Sulfate Esters". Advances in Enzymology and Related Areas of Molecular Biology. pp. 205–35. doi:10.1002/9780470122679.ch5. ISBN 9780470122679. PMID 13744184. {{cite book}}: |journal= ignored (help)
  19. Halkerston ID, Hillman J, Stitch SR (August 1956). "The enzymic hydrolysis of steroid conjugates. I. Sulphatase and β-glucuronidase activity of molluscan extracts". The Biochemical Journal. 63 (4): 705–10. doi:10.1042/bj0630705. PMC 1216242. PMID 13355874.

Further reading
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