View source for Steroid sulfatase

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox gene}}
{{Infobox enzyme
| Name       = Steryl-sulfatase
| EC_number  = 3.1.6.2
| CAS_number = 9025-62-1
| GO_code    =
| image      = 
| width      = 
| caption    =  
}}

'''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.<ref name="entrez">{{cite web | title = Entrez Gene: STS steroid sulfatase (microsomal), arylsulfatase C, isozyme S| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=412}}</ref>

==Reactions==
This enzyme [[catalysis|catalyses]] the following [[chemical reaction]]

: 3β-hydroxyandrost-5-en-17-one 3-sulfate + H<sub>2</sub>O <math>\rightleftharpoons</math> 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).<ref name="MuellerGilligan2015">{{cite journal | vauthors = Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA | title = The Regulation of Steroid Action by Sulfation and Desulfation | journal = Endocrine Reviews | volume = 36 | issue = 5 | pages = 526–63 | date = October 2015 | pmid = 26213785 | pmc = 4591525 | doi = 10.1210/er.2015-1036 }}</ref><ref name="Rižner2016">{{cite journal | vauthors = Rižner TL | title = The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases | journal = Frontiers in Pharmacology | volume = 7 | pages = 30 | year = 2016 | pmid = 26924986 | pmc = 4757672 | doi = 10.3389/fphar.2016.00030 | doi-access = free }}</ref> The encoded protein is found in the [[endoplasmic reticulum]], where it is present as a [[homodimer]].<ref name="entrez"/>

[[File:Estrogenic STS and EST activity.png|thumb|center|425px|Distribution of STS and {{abbrlink|EST|estrogen sulfotransferase}} activities for interconversion of [[estrone]] (E1) and [[estrone sulfate]] (E1S) in adult human tissues.<ref name="pmid12466383">{{cite journal | vauthors = Miki Y, Nakata T, Suzuki T, Darnel AD, Moriya T, Kaneko C, Hidaka K, Shiotsu Y, Kusaka H, Sasano H | display-authors = 6 | title = Systemic distribution of steroid sulfatase and estrogen sulfotransferase in human adult and fetal tissues | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 87 | issue = 12 | pages = 5760–8 | date = December 2002 | pmid = 12466383 | doi = 10.1210/jc.2002-020670 | doi-access = free }}</ref>]]

==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.<ref name="pmid9252398">{{cite journal | vauthors = Alperin ES, Shapiro LJ | title = Characterization of point mutations in patients with X-linked ichthyosis. Effects on the structure and function of the steroid sulfatase protein | journal = The Journal of Biological Chemistry | volume = 272 | issue = 33 | pages = 20756–63 | date = August 1997 | pmid = 9252398 | doi = 10.1074/jbc.272.33.20756 | doi-access = free }}</ref><ref name="pmid15607112">{{cite journal | vauthors = Ghosh D | title = Mutations in X-linked ichthyosis disrupt the active site structure of estrone/DHEA sulfatase | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1739 | issue = 1 | pages = 1–4 | date = December 2004 | pmid = 15607112 | doi = 10.1016/j.bbadis.2004.09.003 | doi-access =  }}</ref> The excessive [[desquamation|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.<ref name="MuellerGilligan2015" />

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.<ref name="pmid32139392">{{cite journal | vauthors = Brcic L, Underwood JF, Kendall KM, Caseras X, Kirov G, Davies W | title = Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank | journal = Journal of Medical Genetics | volume = 57 | issue = 10 |pages = 692–698 | date = Mar 2020 | pmid = 32139392 | doi = 10.1136/jmedgenet-2019-106676 | pmc = 7525778 | doi-access = free }}</ref> Both steroid sulfatase deficiency and common genetic risk variants within STS may confer increased [[atrial fibrillation]] risk.<ref name="Wren_2022">{{cite journal | vauthors = Wren G, Baker E, Underwood J, Humby T, Thompson A, Kirov G, Escott-Price V, Davies W | title = Characterising heart rhythm abnormalities associated with Xp22.31 deletion | journal = Journal of Medical Genetics | volume = 60| issue = 7| pages = 636–643| date = November 2022 | pmid = 36379544 | doi = 10.1136/jmg-2022-108862 | pmc = 10359567 | doi-access = free }}</ref> Cardiac [[arrhythmia]] in STS deficiency may be related to abnormal development of the [[interventricular septum]] or [[interatrial septum]].<ref name="pmid38571328">{{cite journal | vauthors = Wren GH, Davies W | title = Cardiac arrhythmia in individuals with steroid sulfatase deficiency (X-linked ichthyosis): candidate anatomical and biochemical pathways | journal = Essays in Biochemistry | volume = | issue = | pages = | date = April 2024 | pmid = 38571328 | doi = 10.1042/EBC20230098 | url = | doi-access = free | pmc = 11625857 }}</ref> Blood-clotting abnormalities may occur more frequently in males with XLI and female carriers.<ref name="pmid35330591">{{cite journal | vauthors = Brcic L, Wren GH, Underwood JF, Kirov G, Davies W | title = Comorbid Medical Issues in X-Linked Ichthyosis | journal = JID Innovations: Skin Science from Molecules to Population Health | volume = 2 | issue = 3 | pages = 100109 | date = May 2022 | pmid = 35330591 | pmc = 8938907 | doi = 10.1016/j.xjidi.2022.100109 | url = }}</ref> 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.<ref name="pmid37363400">{{cite journal | vauthors = McGeoghan F, Camera E, Maiellaro M, Menon M, Huang M, Dewan P, Ziaj S, Caley MP, Donaldson M, Enright AJ, O'Toole EA | title = RNA sequencing and lipidomics uncovers novel pathomechanisms in recessive X-linked ichthyosis | journal = Frontiers in Molecular Biosciences | volume = 10 | issue = | pages = 1176802 | date = 2023 | pmid = 37363400 | pmc = 10285781 | doi = 10.3389/fmolb.2023.1176802 | doi-access = free | url = }}</ref>

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-dependent condition|androgen-]] and [[estrogen-dependent condition]]s 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.<ref name=":0">{{cite journal | vauthors = Potter BV | title = SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects | journal = Journal of Molecular Endocrinology | volume = 61 | issue = 2 | pages = T233–T252 | date = August 2018 | pmid = 29618488 | doi = 10.1530/JME-18-0045 | url = https://jme.bioscientifica.com/view/journals/jme/61/2/JME-18-0045.xml | doi-access = free }}</ref> The non-steroidal drug [[Irosustat]] has been the most studied to date.

==Inhibitors==
[[Enzyme inhibitor|Inhibitor]]s of STS include [[irosustat]], [[estrone sulfamate]] (EMATE), [[estradiol sulfamate]] (E2MATE), and [[danazol]].<ref name="pmid25843211">{{cite journal | vauthors = Thomas MP, Potter BV | title = Estrogen ''O''-sulfamates and their analogues: Clinical steroid sulfatase inhibitors with broad potential | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 153 | pages = 160–9 | date = September 2015 | pmid = 25843211 | doi = 10.1016/j.jsbmb.2015.03.012 | s2cid = 24116740 }}</ref><ref name="pmid6238495">{{cite journal | vauthors = Carlström K, Döberl A, Pousette A, Rannevik G, Wilking N | title = Inhibition of steroid sulfatase activity by danazol | journal = Acta Obstetricia et Gynecologica Scandinavica Supplement | volume = 123 | pages = 107–11 | year = 1984 | pmid = 6238495 | doi = 10.3109/00016348409156994 | s2cid = 45817485 }}</ref> The most potent inhibitors are based around the aryl sulfamate pharmacophore<ref>{{cite journal | vauthors = Thomas MP, Potter BV | title = Discovery and Development of the Aryl ''O''-Sulfamate Pharmacophore for Oncology and Women's Health | journal = Journal of Medicinal Chemistry | volume = 58 | issue = 19 | pages = 7634–58 | date = October 2015 | pmid = 25992880 | pmc = 5159624 | doi = 10.1021/acs.jmedchem.5b00386 }}</ref> and it is thought that such compounds irreversibly modify the active site formylglycine residue of steroid sulfatase.<ref name=":0" />

==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 [[List of enzymes|systematic name]] ''steryl-sulfate sulfohydrolase''.<ref>{{cite journal | vauthors = Roy AB | title = The steroid sulphatase of ''Patella vulgata'' | journal = Biochimica et Biophysica Acta | volume = 15 | issue = 2 | pages = 300–1 | date = October 1954 | pmid = 13208702 | pmc = 1274509 | doi = 10.1016/0006-3002(54)90078-5 }}</ref><ref>{{cite book | vauthors = Roy AB | chapter = The Synthesis and Hydrolysis of Sulfate Esters | title = Advances in Enzymology and Related Areas of Molecular Biology | journal = Advances in Enzymology and Related Subjects of Biochemistry | series = Advances in Enzymology - and Related Areas of Molecular Biology | volume = 22 | pages = 205–35 | date = 1960 | doi = 10.1002/9780470122679.ch5 | pmid = 13744184 | isbn = 9780470122679 }}</ref><ref>{{cite journal | vauthors = Halkerston ID, Hillman J, Stitch SR | title = The enzymic hydrolysis of steroid conjugates. I. Sulphatase and β-glucuronidase activity of molluscan extracts | journal = The Biochemical Journal | volume = 63 | issue = 4 | pages = 705–10 | date = August 1956 | pmid = 13355874 | pmc = 1216242 | doi = 10.1042/bj0630705 }}</ref>

== See also ==
* [[Steroidogenic enzyme]]
* [[Steroid sulfotransferase]]
* [[Estrogen sulfotransferase]]

== References ==
{{Reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Elias PM, Crumrine D, Rassner U, Hachem JP, Menon GK, Man W, Choy MH, Leypoldt L, Feingold KR, Williams ML | display-authors = 6 | title = Basis for abnormal desquamation and permeability barrier dysfunction in RXLI | journal = The Journal of Investigative Dermatology | volume = 122 | issue = 2 | pages = 314–9 | date = February 2004 | pmid = 15009711 | doi = 10.1046/j.1523-1747.2003.22258.x | doi-access = free }}
* {{cite journal | vauthors = Basler E, Grompe M, Parenti G, Yates J, Ballabio A | title = Identification of point mutations in the steroid sulfatase gene of three patients with X-linked ichthyosis | journal = American Journal of Human Genetics | volume = 50 | issue = 3 | pages = 483–91 | date = March 1992 | pmid = 1539590 | pmc = 1684279 }}
* {{cite journal | vauthors = Shankaran R, Ameen M, Daniel WL, Davidson RG, Chang PL | title = Characterization of arylsulfatase C isozymes from human liver and placenta | journal = Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology | volume = 1078 | issue = 2 | pages = 251–7 | date = June 1991 | pmid = 2065092 | doi = 10.1016/0167-4838(91)90566-I }}
* {{cite journal | vauthors = Stein C, Hille A, Seidel J, Rijnbout S, Waheed A, Schmidt B, Geuze H, von Figura K | display-authors = 6 | title = Cloning and expression of human steroid-sulfatase. Membrane topology, glycosylation, and subcellular distribution in BHK-21 cells | journal = The Journal of Biological Chemistry | volume = 264 | issue = 23 | pages = 13865–72 | date = August 1989 | doi = 10.1016/S0021-9258(18)80080-1 | pmid = 2668275 | doi-access = free }}
* {{cite journal | vauthors = Kawano J, Kotani T, Ohtaki S, Minamino N, Matsuo H, Oinuma T, Aikawa E | title = Characterization of rat and human steroid sulfatases | journal = Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology | volume = 997 | issue = 3 | pages = 199–205 | date = August 1989 | pmid = 2765556 | doi = 10.1016/0167-4838(89)90187-8 }}
* {{cite journal | vauthors = Yen PH, Allen E, Marsh B, Mohandas T, Wang N, Taggart RT, Shapiro LJ | s2cid = 23353934 | title = Cloning and expression of steroid sulfatase cDNA and the frequent occurrence of deletions in STS deficiency: implications for X-Y interchange | journal = Cell | volume = 49 | issue = 4 | pages = 443–54 | date = May 1987 | pmid = 3032454 | doi = 10.1016/0092-8674(87)90447-8 }}
* {{cite journal | vauthors = Conary JT, Lorkowski G, Schmidt B, Pohlmann R, Nagel G, Meyer HE, Krentler C, Cully J, Hasilik A, von Figura K | display-authors = 6 | title = Genetic heterogeneity of steroid sulfatase deficiency revealed with cDNA for human steroid sulfatase | journal = Biochemical and Biophysical Research Communications | volume = 144 | issue = 2 | pages = 1010–7 | date = April 1987 | pmid = 3034252 | doi = 10.1016/S0006-291X(87)80064-5 }}
* {{cite journal | vauthors = Ballabio A, Parenti G, Carrozzo R, Coppa G, Felici L, Migliori V, Silengo M, Franceschini P, Andria G | display-authors = 6 | title = 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 | journal = Clinical Genetics | volume = 34 | issue = 1 | pages = 31–7 | date = July 1988 | pmid = 3165728 | doi = 10.1111/j.1399-0004.1988.tb02612.x | s2cid = 39954996 }}
* {{cite journal | vauthors = Yen PH, Marsh B, Allen E, Tsai SP, Ellison J, Connolly L, Neiswanger K, Shapiro LJ | s2cid = 42065481 | display-authors = 6 | title = The human X-linked steroid sulfatase gene and a Y-encoded pseudogene: evidence for an inversion of the Y chromosome during primate evolution | journal = Cell | volume = 55 | issue = 6 | pages = 1123–35 | date = December 1988 | pmid = 3203382 | doi = 10.1016/0092-8674(88)90257-7 }}
* {{cite journal | vauthors = Chang PL, Varey PA, Rosa NE, Ameen M, Davidson RG | title = Association of steroid sulfatase with one of the arylsulfatase C isozymes in human fibroblasts | journal = The Journal of Biological Chemistry | volume = 261 | issue = 31 | pages = 14443–7 | date = November 1986 | doi = 10.1016/S0021-9258(18)66889-9 | pmid = 3464600 | doi-access = free }}
* {{cite journal | vauthors = Munroe DG, Chang PL | title = Tissue-specific expression of human arylsulfatase-C isozymes and steroid sulfatase | journal = American Journal of Human Genetics | volume = 40 | issue = 2 | pages = 102–14 | date = February 1987 | pmid = 3471087 | pmc = 1684069 }}
* {{cite journal | vauthors = Müller CR, Wahlström J, Ropers HH | s2cid = 23372914 | title = Further evidence for the assignment of the steroid sulfatase X-linked ichthyosis locus to the telomer of Xp | journal = Human Genetics | volume = 58 | issue = 4 | pages = 446–447 | year = 1982 | pmid = 6948769 | doi = 10.1007/bf00282842 }}
* {{cite journal | vauthors = Migeon BR, Shapiro LJ, Norum RA, Mohandas T, Axelman J, Dabora RL | s2cid = 4361097 | title = Differential expression of steroid sulphatase locus on active and inactive human X chromosome | journal = Nature | volume = 299 | issue = 5886 | pages = 838–40 | date = October 1982 | pmid = 6957717 | doi = 10.1038/299838a0 | bibcode = 1982Natur.299..838M }}
* {{cite journal | vauthors = Bonaldo MF, Lennon G, Soares MB | title = Normalization and subtraction: two approaches to facilitate gene discovery | journal = Genome Research | volume = 6 | issue = 9 | pages = 791–806 | date = September 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 | doi-access = free }}
* {{cite journal | vauthors = Alperin ES, Shapiro LJ | title = Characterization of point mutations in patients with X-linked ichthyosis. Effects on the structure and function of the steroid sulfatase protein | journal = The Journal of Biological Chemistry | volume = 272 | issue = 33 | pages = 20756–63 | date = August 1997 | pmid = 9252398 | doi = 10.1074/jbc.272.33.20756 | doi-access = free }}
* {{cite journal | vauthors = Sugawara T, Shimizu H, Hoshi N, Fujimoto Y, Nakajima A, Fujimoto S | title = PCR diagnosis of X-linked ichthyosis: identification of a novel mutation (E560P) of the steroid sulfatase gene | journal = Human Mutation | volume = 15 | issue = 3 | pages = 296 | date = March 2000 | pmid = 10679952 | doi = 10.1002/(SICI)1098-1004(200003)15:3<296::AID-HUMU17>3.0.CO;2-# | s2cid = 196599371 }}
* {{cite journal | vauthors = Oyama N, Satoh M, Iwatsuki K, Kaneko F | title = Novel point mutations in the steroid sulfatase gene in patients with X-linked ichthyosis: transfection analysis using the mutated genes | journal = The Journal of Investigative Dermatology | volume = 114 | issue = 6 | pages = 1195–9 | date = June 2000 | pmid = 10844566 | doi = 10.1046/j.1523-1747.2000.00004.x | doi-access = free }}
* {{cite journal | vauthors = Jimenez Vaca AL, Valdes-Flores M, Rivera-Vega MR, González-Huerta LM, Kofman-Alfaro SH, Cuevas-Covarrubias SA | title = Deletion pattern of the STS gene in X-linked ichthyosis in a Mexican population | journal = Molecular Medicine | volume = 7 | issue = 12 | pages = 845–9 | date = December 2001 | pmid = 11844872 | pmc = 1950010 | doi = 10.1007/BF03401976 }}
* {{cite journal | vauthors = Hoffmann R, Rot A, Niiyama S, Billich A | title = Steroid sulfatase in the human hair follicle concentrates in the dermal papilla | journal = The Journal of Investigative Dermatology | volume = 117 | issue = 6 | pages = 1342–8 | date = December 2001 | pmid = 11886493 | doi = 10.1046/j.0022-202x.2001.01547.x | doi-access = free }}
* {{cite journal | vauthors = Matsuoka R, Yanaihara A, Saito H, Furusawa Y, Toma Y, Shimizu Y, Yanaihara T, Okai T | s2cid = 11872655 | display-authors = 6 | title = Regulation of estrogen activity in human endometrium: effect of IL-1β on steroid sulfatase activity in human endometrial stromal cells | journal = Steroids | volume = 67 | issue = 7 | pages = 655–9 | date = June 2002 | pmid = 11996939 | doi = 10.1016/S0039-128X(02)00016-8 }}
{{refend}}

== External links ==
* {{MeshName|Steryl-Sulfatase}}

{{PDB Gallery|geneid=412}}
{{Esterases}}
{{Steroid metabolism enyzmes}}
{{Portal bar|Biology|border=no}}

[[Category:EC 3.1.6]]
[[Category:Endocrinology]]