Steroid sulfatase explained

Steryl-sulfatase
Ec Number:	3.1.6.2
Cas Number:	9025-62-1

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.^[1]

Reactions

This enzyme catalyses the following chemical reaction

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

\rightleftharpoons 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).^{[2] [3]} The encoded protein is found in the endoplasmic reticulum, where it is present as a homodimer.^[1]

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.^{[4] [5]} 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.

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.^[6] Both steroid sulfatase deficiency and common genetic risk variants within STS may confer increased atrial fibrillation risk.^[7] Cardiac arrhythmia in STS deficiency may be related to abnormal development of the interventricular septum or interatrial septum.^[8] Blood-clotting abnormalities may occur more frequently in males with XLI and female carriers.^[9] 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.^[10]

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.^[11] 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.^{[12] [13]} The most potent inhibitors are based around the aryl sulfamate pharmacophore^[14] and it is thought that such compounds irreversibly modify the active site formylglycine residue of steroid sulfatase.

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.^{[15] [16] [17]}

See also

• Steroidogenic enzyme
• Steroid sulfotransferase
• Estrogen sulfotransferase

Further reading

• Elias PM, Crumrine D, Rassner U, Hachem JP, Menon GK, Man W, Choy MH, Leypoldt L, Feingold KR, Williams ML . 6 . Basis for abnormal desquamation and permeability barrier dysfunction in RXLI . The Journal of Investigative Dermatology . 122 . 2 . 314–9 . February 2004 . 15009711 . 10.1046/j.1523-1747.2003.22258.x . free .
• Basler E, Grompe M, Parenti G, Yates J, Ballabio A . Identification of point mutations in the steroid sulfatase gene of three patients with X-linked ichthyosis . American Journal of Human Genetics . 50 . 3 . 483–91 . March 1992 . 1539590 . 1684279 .
• Shankaran R, Ameen M, Daniel WL, Davidson RG, Chang PL . Characterization of arylsulfatase C isozymes from human liver and placenta . Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology . 1078 . 2 . 251–7 . June 1991 . 2065092 . 10.1016/0167-4838(91)90566-I .
• Stein C, Hille A, Seidel J, Rijnbout S, Waheed A, Schmidt B, Geuze H, von Figura K . 6 . Cloning and expression of human steroid-sulfatase. Membrane topology, glycosylation, and subcellular distribution in BHK-21 cells . The Journal of Biological Chemistry . 264 . 23 . 13865–72 . August 1989 . 10.1016/S0021-9258(18)80080-1 . 2668275 . free .
• Kawano J, Kotani T, Ohtaki S, Minamino N, Matsuo H, Oinuma T, Aikawa E . Characterization of rat and human steroid sulfatases . Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology . 997 . 3 . 199–205 . August 1989 . 2765556 . 10.1016/0167-4838(89)90187-8 .
• Yen PH, Allen E, Marsh B, Mohandas T, Wang N, Taggart RT, Shapiro LJ . 23353934 . Cloning and expression of steroid sulfatase cDNA and the frequent occurrence of deletions in STS deficiency: implications for X-Y interchange . Cell . 49 . 4 . 443–54 . May 1987 . 3032454 . 10.1016/0092-8674(87)90447-8 .
• Conary JT, Lorkowski G, Schmidt B, Pohlmann R, Nagel G, Meyer HE, Krentler C, Cully J, Hasilik A, von Figura K . 6 . Genetic heterogeneity of steroid sulfatase deficiency revealed with cDNA for human steroid sulfatase . Biochemical and Biophysical Research Communications . 144 . 2 . 1010–7 . April 1987 . 3034252 . 10.1016/S0006-291X(87)80064-5 .
• Ballabio A, Parenti G, Carrozzo R, Coppa G, Felici L, Migliori V, Silengo M, Franceschini P, Andria G . 6 . X/Y translocation in a family with X-linked ichthyosis, chondrodysplasia punctata, and mental retardation: DNA analysis reveals deletion of the steroid sulphatase gene and translocation of its Y pseudogene . Clinical Genetics . 34 . 1 . 31–7 . July 1988 . 3165728 . 10.1111/j.1399-0004.1988.tb02612.x . 39954996 .
• Yen PH, Marsh B, Allen E, Tsai SP, Ellison J, Connolly L, Neiswanger K, Shapiro LJ . 42065481 . 6 . The human X-linked steroid sulfatase gene and a Y-encoded pseudogene: evidence for an inversion of the Y chromosome during primate evolution . Cell . 55 . 6 . 1123–35 . December 1988 . 3203382 . 10.1016/0092-8674(88)90257-7 .
• Chang PL, Varey PA, Rosa NE, Ameen M, Davidson RG . Association of steroid sulfatase with one of the arylsulfatase C isozymes in human fibroblasts . The Journal of Biological Chemistry . 261 . 31 . 14443–7 . November 1986 . 10.1016/S0021-9258(18)66889-9 . 3464600 . free .
• Munroe DG, Chang PL . Tissue-specific expression of human arylsulfatase-C isozymes and steroid sulfatase . American Journal of Human Genetics . 40 . 2 . 102–14 . February 1987 . 3471087 . 1684069 .
• Müller CR, Wahlström J, Ropers HH . 23372914 . Further evidence for the assignment of the steroid sulfatase X-linked ichthyosis locus to the telomer of Xp . Human Genetics . 58 . 4 . 446–447 . 1982 . 6948769 . 10.1007/bf00282842 .
• Migeon BR, Shapiro LJ, Norum RA, Mohandas T, Axelman J, Dabora RL . 4361097 . Differential expression of steroid sulphatase locus on active and inactive human X chromosome . Nature . 299 . 5886 . 838–40 . October 1982 . 6957717 . 10.1038/299838a0 . 1982Natur.299..838M .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Alperin ES, Shapiro LJ . 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 . August 1997 . 9252398 . 10.1074/jbc.272.33.20756 . free .
• Sugawara T, Shimizu H, Hoshi N, Fujimoto Y, Nakajima A, Fujimoto S . PCR diagnosis of X-linked ichthyosis: identification of a novel mutation (E560P) of the steroid sulfatase gene . Human Mutation . 15 . 3 . 296 . March 2000 . 10679952 . 10.1002/(SICI)1098-1004(200003)15:3<296::AID-HUMU17>3.0.CO;2-# . 196599371 .
• Oyama N, Satoh M, Iwatsuki K, Kaneko F . Novel point mutations in the steroid sulfatase gene in patients with X-linked ichthyosis: transfection analysis using the mutated genes . The Journal of Investigative Dermatology . 114 . 6 . 1195–9 . June 2000 . 10844566 . 10.1046/j.1523-1747.2000.00004.x . free .
• Jimenez Vaca AL, Valdes-Flores M, Rivera-Vega MR, González-Huerta LM, Kofman-Alfaro SH, Cuevas-Covarrubias SA . Deletion pattern of the STS gene in X-linked ichthyosis in a Mexican population . Molecular Medicine . 7 . 12 . 845–9 . December 2001 . 11844872 . 1950010 . 10.1007/BF03401976 .
• Hoffmann R, Rot A, Niiyama S, Billich A . Steroid sulfatase in the human hair follicle concentrates in the dermal papilla . The Journal of Investigative Dermatology . 117 . 6 . 1342–8 . December 2001 . 11886493 . 10.1046/j.0022-202x.2001.01547.x . free .
• Matsuoka R, Yanaihara A, Saito H, Furusawa Y, Toma Y, Shimizu Y, Yanaihara T, Okai T . 11872655 . 6 . Regulation of estrogen activity in human endometrium: effect of IL-1β on steroid sulfatase activity in human endometrial stromal cells . Steroids . 67 . 7 . 655–9 . June 2002 . 11996939 . 10.1016/S0039-128X(02)00016-8 .

Notes and References

1. Web site: Entrez Gene: STS steroid sulfatase (microsomal), arylsulfatase C, isozyme S.
2. Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA . The Regulation of Steroid Action by Sulfation and Desulfation . Endocrine Reviews . 36 . 5 . 526–63 . October 2015 . 26213785 . 4591525 . 10.1210/er.2015-1036 .
3. Rižner TL . The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases . Frontiers in Pharmacology . 7 . 30 . 2016 . 26924986 . 4757672 . 10.3389/fphar.2016.00030 . free .
4. Alperin ES, Shapiro LJ . 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 . August 1997 . 9252398 . 10.1074/jbc.272.33.20756 . free .
5. Ghosh D . 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 . December 2004 . 15607112 . 10.1016/j.bbadis.2004.09.003 .
6. Brcic L, Underwood JF, Kendall KM, Caseras X, Kirov G, Davies W . 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 . Mar 2020 . 32139392 . 10.1136/jmedgenet-2019-106676 . 7525778 . free .
7. Wren G, Baker E, Underwood J, Humby T, Thompson A, Kirov G, Escott-Price V, Davies W . Characterising heart rhythm abnormalities associated with Xp22.31 deletion . Journal of Medical Genetics . 60. 7. 636–643. November 2022 . 36379544 . 10.1136/jmg-2022-108862 . 10359567 . free .
8. Wren GH, Davies W . Cardiac arrhythmia in individuals with steroid sulfatase deficiency (X-linked ichthyosis): candidate anatomical and biochemical pathways . Essays in Biochemistry . April 2024 . 38571328 . 10.1042/EBC20230098 . free .
9. Brcic L, Wren GH, Underwood JF, Kirov G, Davies W . Comorbid Medical Issues in X-Linked Ichthyosis . JID Innovations: Skin Science from Molecules to Population Health . 2 . 3 . 100109 . May 2022 . 35330591 . 8938907 . 10.1016/j.xjidi.2022.100109 .
10. McGeoghan F, Camera E, Maiellaro M, Menon M, Huang M, Dewan P, Ziaj S, Caley MP, Donaldson M, Enright AJ, O'Toole EA . RNA sequencing and lipidomics uncovers novel pathomechanisms in recessive X-linked ichthyosis . Frontiers in Molecular Biosciences . 10 . 1176802 . 2023 . 37363400 . 10285781 . 10.3389/fmolb.2023.1176802 . free .
11. Potter BV . SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects . Journal of Molecular Endocrinology . 61 . 2 . T233–T252 . August 2018 . 29618488 . 10.1530/JME-18-0045 . free .
12. Thomas MP, Potter BV . Estrogen O-sulfamates and their analogues: Clinical steroid sulfatase inhibitors with broad potential . The Journal of Steroid Biochemistry and Molecular Biology . 153 . 160–9 . September 2015 . 25843211 . 10.1016/j.jsbmb.2015.03.012 . 24116740 .
13. Carlström K, Döberl A, Pousette A, Rannevik G, Wilking N . Inhibition of steroid sulfatase activity by danazol . Acta Obstetricia et Gynecologica Scandinavica Supplement . 123 . 107–11 . 1984 . 6238495 . 10.3109/00016348409156994 . 45817485 .
14. Thomas MP, Potter BV . Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women's Health . Journal of Medicinal Chemistry . 58 . 19 . 7634–58 . October 2015 . 25992880 . 5159624 . 10.1021/acs.jmedchem.5b00386 .
15. Roy AB . The steroid sulphatase of Patella vulgata . Biochimica et Biophysica Acta . 15 . 2 . 300–1 . October 1954 . 13208702 . 1274509 . 10.1016/0006-3002(54)90078-5 .
16. Book: Roy AB . The Synthesis and Hydrolysis of Sulfate Esters . Advances in Enzymology and Related Areas of Molecular Biology . Advances in Enzymology and Related Subjects of Biochemistry . Advances in Enzymology - and Related Areas of Molecular Biology . 22 . 205–35 . 1960 . 10.1002/9780470122679.ch5 . 13744184 . 9780470122679 .
17. Halkerston ID, Hillman J, Stitch SR . The enzymic hydrolysis of steroid conjugates. I. Sulphatase and β-glucuronidase activity of molluscan extracts . The Biochemical Journal . 63 . 4 . 705–10 . August 1956 . 13355874 . 1216242 . 10.1042/bj0630705 .