Steroid sulfatase

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STS
Protein STS PDB 1p49.png
Available structures
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Identifiers
Aliases STS , ARSC, ARSC2, ARSC1, ASC, ES, SSDD, XLI, Steroid sulfatase (microsomal), isozyme S, steroid sulfatase
External IDs OMIM: 300747 HomoloGene: 47918 GeneCards: STS
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SpeciesHumanMouse
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Location (UCSC) Chr X: 7.15 – 7.8 Mb n/a
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Steryl-sulfatase
Identifiers
EC no. 3.1.6.2
CAS no. 9025-62-1
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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]

Contents

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 EST activities for interconversion of estrone (E1) and estrone sulfate (E1S) in adult human tissues. Estrogenic STS and EST activity.png
Distribution of STS and EST activities for interconversion of estrone (E1) and estrone sulfate (E1S) in adult human tissues.

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

Related Research Articles

<span class="mw-page-title-main">X-linked ichthyosis</span> Medical condition

X-linked ichthyosis is a skin condition caused by the hereditary deficiency of the steroid sulfatase (STS) enzyme that affects 1 in 2000 to 1 in 6000 males. XLI manifests with dry, scaly skin and is due to deletions or mutations in the STS gene. XLI can also occur in the context of larger deletions causing contiguous gene syndromes. Treatment is largely aimed at alleviating the skin symptoms. The term is from the Ancient Greek 'ichthys' meaning 'fish'.

<span class="mw-page-title-main">Arylsulfatase A</span>

Arylsulfatase A is an enzyme that breaks down sulfatides, namely cerebroside 3-sulfate into cerebroside and sulfate. In humans, arylsulfatase A is encoded by the ARSA gene.

<span class="mw-page-title-main">Sulfatase</span> Class of enzymes

Sulfatases EC 3.1.6.- are enzymes of the esterase class that catalyze the hydrolysis of sulfate esters. These may be found on a range of substrates, including steroids, carbohydrates and proteins. Sulfate esters may be formed from various alcohols and amines. In the latter case the resultant N-sulfates can also be termed sulfamates.

<span class="mw-page-title-main">Arylsulfatase B</span> Mammalian protein found in Homo sapiens

Arylsulfatase B is an enzyme associated with mucopolysaccharidosis VI.

<span class="mw-page-title-main">Arylsulfatase</span>

Arylsulfatase (EC 3.1.6.1, sulfatase, nitrocatechol sulfatase, phenolsulfatase, phenylsulfatase, p-nitrophenyl sulfatase, arylsulfohydrolase, 4-methylumbelliferyl sulfatase, estrogen sulfatase) is a type of sulfatase enzyme with systematic name aryl-sulfate sulfohydrolase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Iduronate-2-sulfatase</span> Class of enzymes

Iduronate 2-sulfatase is a sulfatase enzyme associated with Hunter syndrome. It catalyses hydrolysis of the 2-sulfate groups of the L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate and heparin.

<span class="mw-page-title-main">Galactosamine-6 sulfatase</span> Protein-coding gene in the species Homo sapiens

N-acetylgalactosamine-6-sulfatase is an enzyme that, in humans, is encoded by the GALNS gene.

<span class="mw-page-title-main">SULT1E1</span> Protein-coding gene in the species Homo sapiens

Estrogen sulfotransferase is an enzyme that in humans is encoded by the SULT1E1 gene.

<span class="mw-page-title-main">Estrone sulfate</span> Chemical compound

Estrone sulfate, also known as E1S, E1SO4 and estrone 3-sulfate, is a natural, endogenous steroid and an estrogen ester and conjugate.

X-linked recessive chondrodysplasia punctata is a type of chondrodysplasia punctata that can involve the skin, hair, and cause short stature with skeletal abnormalities, cataracts, and deafness.

<span class="mw-page-title-main">Arylsulfatase E</span> Protein-coding gene in the species Homo sapiens

Arylsulfatase E, also known as ARSE, is an enzyme that, in humans, is encoded by the ARSE gene.

Sulfate conjugates are a heterogeneous class of polar, anionic organosulfate compounds containing an ester of sulfuric acid. Sulfate conjugates commonly result from the metabolic conjugation of endogenous and exogenous compounds with sulfate (-OSO3).

<span class="mw-page-title-main">Formylglycine-generating enzyme</span>

Formylglycine-generating enzyme (FGE), located at 3p26.1 in humans, is the name for an enzyme present in the endoplasmic reticulum that catalyzes the conversion of cysteine to formylglycine (fGly). There are two main classes of FGE, aerobic and anaerobic. FGE activates sulfatases, which are essential for the degradation of sulfate esters. The catalytic activity of sulfatases is dependent upon a formylglycine residue in the active site.

A steroidogenesis inhibitor, also known as a steroid biosynthesis inhibitor, is a type of drug which inhibits one or more of the enzymes that are involved in the process of steroidogenesis, the biosynthesis of endogenous steroids and steroid hormones. They may inhibit the production of cholesterol and other sterols, sex steroids such as androgens, estrogens, and progestogens, corticosteroids such as glucocorticoids and mineralocorticoids, and neurosteroids. They are used in the treatment of a variety of medical conditions that depend on endogenous steroids.

<span class="mw-page-title-main">Estradiol sulfate</span> Chemical compound

Estradiol sulfate (E2S), or 17β-estradiol 3-sulfate, is a natural, endogenous steroid and an estrogen ester. E2S itself is biologically inactive, but it can be converted by steroid sulfatase into estradiol, which is a potent estrogen. Simultaneously, estrogen sulfotransferases convert estradiol to E2S, resulting in an equilibrium between the two steroids in various tissues. Estrone and E2S are the two immediate metabolic sources of estradiol. E2S can also be metabolized into estrone sulfate (E1S), which in turn can be converted into estrone and estradiol. Circulating concentrations of E2S are much lower than those of E1S. High concentrations of E2S are present in breast tissue, and E2S has been implicated in the biology of breast cancer via serving as an active reservoir of estradiol.

<span class="mw-page-title-main">Irosustat</span> Chemical compound

Irosustat is an orally active, irreversible, nonsteroidal inhibitor of steroid sulfatase (STS) and member of the aryl sulfamate ester class of drugs that was under development by Sterix Ltd and Ipsen for the treatment of hormone-sensitive cancers such as breast cancer, prostate cancer, and endometrial cancer but has not yet been marketed. The drug was first designed and synthesized in the group of Professor Barry V L Potter at the Department of Pharmacy & Pharmacology, University of Bath, working together with Professor Michael J. Reed at Imperial College, London and its initial development was undertaken through the university spin-out company Sterix Ltd and overseen by Cancer Research UK (CRUK). Results of the "first-in-class" clinical trial in breast cancer of an STS inhibitor in humans were published in 2006 and dose optimisation studies and further clinical data have been reported.

<span class="mw-page-title-main">Estradiol sulfamate</span> Steroid sulfatase inhibitor under development

Estradiol sulfamate, or estradiol-3-O-sulfamate, is a steroid sulfatase (STS) inhibitor which is under development for the treatment of endometriosis. It is the C3 sulfamate ester of estradiol, and was originally thought to be a prodrug of estradiol. The drug was first synthesized as an STS inhibitor along with its oxidized version estrone 3-O-sulfamate (EMATE) in the group of Professor Barry V L Potter at the University of Bath, UK, working together with Professor Michael J Reed at Imperial College, London and was found to be highly estrogenic in rodents. Such aryl sulfamate esters were shown to be "first-in-class" highly potent active site-directed irreversible STS inhibitors. Compounds of this class are thought to irreversibly modify the active site formylglycine residue of STS. The drug shows profoundly reduced susceptibility to first-pass metabolism relative to estradiol, and was believed to be the first "potent" estradiol prodrug to be discovered. It was clinically investigated for possible use as an estrogen for indications like hormonal contraception and menopausal hormone therapy. However, it showed no estrogenic effects in women. The potent non-estrogenic clinical STS inhibitor Irosustat (STX64/667-Coumate) was used to explore the possibility that STS might be responsible for the hydrolysis of estrogen sulphamates. Results demonstrated convincingly that STS is the enzyme responsible for the removal of the sulfamoyl group from estrogen sulfamates and has a crucial role in regulating the estrogenicity associated with this class of drug. Thus, STS inhibition blocks the conversion of E2MATE into estradiol and thereby abolishes its estrogenicity in humans. Irosustat has completed a number of clinical trials in oncology as an STS inhibitor currently up to Phase II.

<span class="mw-page-title-main">Estrone sulfamate</span> Chemical compound

Estrone sulfamate, or estrone-3-O-sulfamate, is a steroid sulfatase (STS) inhibitor which has not yet been marketed. It is the C3 sulfamate ester of the estrogen estrone. Unlike other estrogen esters however, EMATE is not an effective prodrug of estrogens. A closely related compound is estradiol sulfamate (E2MATE), which is extensively metabolized into EMATE and has similar properties to it.

<span class="mw-page-title-main">Estrone phosphate</span> Chemical compound

Estrone phosphate (E1P), or estrone 3-phosphate, is an estrogen and steroid sulfatase inhibitor which was never marketed. It has similar affinity for steroid sulfatase as estrone sulfate and acts as a competitive inhibitor of the enzyme. In contrast to estrone sulfate however, it is not hydrolyzed by steroid sulfatase and is instead metabolized by phosphatases.

<span class="mw-page-title-main">2-Methoxyestradiol disulfamate</span> Chemical compound

2-Methoxyestradiol disulfamate is a synthetic, oral active anti-cancer medication which was previously under development for potential clinical use. It has improved potency, low metabolism, and good pharmacokinetic properties relative to 2-methoxyestradiol (2-MeO-E2). It is also a potent inhibitor of steroid sulfatase, the enzyme that catalyzes the desulfation of steroids such as estrone sulfate and dehydroepiandrosterone sulfate (DHEA-S).

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000101846 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 "Entrez Gene: STS steroid sulfatase (microsomal), arylsulfatase C, isozyme S".
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  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.
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  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