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The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases

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The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Frontiers - Publisher Connector REVIEW published: 18 February 2016 doi: 10.3389/fphar.2016.00030 The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases Tea Lanišnik Rižner * Faculty of Medicine, Institute of Biochemistry, University of Ljubljana, Ljubljana, Slovenia Gynecological diseases such as endometriosis, adenomyosis and uterine fibroids, and gynecological cancers including endometrial cancer and ovarian cancer, affect a large proportion of women. These diseases are estrogen dependent, and their progression often depends on local estrogen formation. In peripheral tissues, estrogens can be formed from the inactive precursors dehydroepiandrosterone sulfate and estrone sulfate. Sulfatase and sulfotransferases have pivotal roles in these processes, where sulfatase hydrolyzes estrone sulfate to estrone, and dehydroepiandrosterone sulfate to dehydroepiandrosterone, and sulfotransferases catalyze the reverse reactions. Further activation of estrone to the most potent estrogen, estradiol, is catalyzed by 17-ketosteroid reductases, while estradiol can also be formed from dehydroepiandrosterone by the sequential actions of 3β-hydroxysteroid Edited by: dehydrogenase-4-isomerase, aromatase, and 17-ketosteroid reductase. This review Ajay Sharma, Chapman University School of introduces the sulfatase and sulfotransferase enzymes, in terms of their structures and Pharmacy, USA reaction mechanisms, and the regulation and different transcripts of their genes, together Reviewed by: with the importance of their currently known single nucleotide polymorphisms. Data Chris J. Van Koppen, ElexoPharm GmbH, Germany on expression of sulfatase and sulfotransferases in gynecological diseases are also Partha Krishnamurthy, reviewed. There are often unchanged mRNA and protein levels in diseased tissue, University of Kansas Medical Center, with higher sulfatase activities in cancerous endometrium, ovarian cancer cell lines, USA and adenomyosis. This can be indicative of a disturbed balance between the sulfatase *Correspondence: Tea Lanišnik Rižner and sulfotransferases enzymes, defining the potential for sulfatase as a drug target [email protected] for treatment of gynecological diseases. Finally, clinical trials with sulfatase inhibitors are discussed, where two inhibitors have already concluded phase II trials, although Specialty section: This article was submitted to so far with no convincing clinical outcomes for patients with endometrial cancer and Experimental Pharmacology and Drug endometriosis. Discovery, a section of the journal Keywords: endometrial cancer, endometriosis, adenomyosis, uterine fibroids, estrogen formation, estrone sulfate, Frontiers in Pharmacology dehydroepiandrosterone sulfate Received: 23 November 2015 Accepted: 03 February 2016 Published: 18 February 2016 STEROID SULFATASE Citation: The formation and hydrolysis of steroid sulfates by the steroid sulfotransferase (SULT) and Rižner TL (2016) The Important Roles of Steroid Sulfatase and steroid sulfatase (STS) enzymes, respectively, represent important mechanisms in the regulation Sulfotransferases in Gynecological of the biological activities of many steroid hormones (Purohit et al., 1998). STS (E.C. 3.1.6.2.) Diseases. Front. Pharmacol. 7:30. hydrolyzes estrone sulfate (E1-S) and dehydroepiandrosterone sulfate (DHEA-S) to E1 and doi: 10.3389/fphar.2016.00030 DHEA, respectively (Figure 1), as well as cholesterol sulfate and pregnenolone sulfate to their Frontiers in Pharmacology | www.frontiersin.org 1 February 2016 | Volume 7 | Article 30 Rižner The Estrone Sulfatase Pathway in Gynecological Diseases FIGURE 1 | The roles of the STS and SULT enzymes in local estrogen biosynthesis. Synthesis of E2 from DHEA-S by the action of steroid sulfatase (STS), 3β-hydroxysteroid dehydrogenase-4-isomerase (HSD3B1, HSD3B2), aromatase (CYP19A1) and 17-ketosteroid reductase (HSD17B1) or aldo-keto reductase 1C3 (AKR1C3) and CYP19A1; and from E1-S by the action of STS and HSD17B1. Sulfotransferases 2A1 (SULT2A1) and SULT2B1 catalyze the conjugation of DHEA, and SULT1E1 catalyzes the conjugation of E1. Oxidation of E2 to E1 is catalyzed by HSD17B2. Kinetics characterization has revealed that purified STS can corresponding unconjugated forms. The sulfatase protein family hydrolyze DHEA-S and E1-S with µM Km values (Hernandez- includes 17 different human sulfatases, where only STS act on Guzman et al., 2001; Table 1). steroid sulfates (Mueller et al., 2015). The STS gene has been localized to the X chromosome STS has been found in the membranes of the endoplasmic (Xp22.31), and it spans 146 kb, includes 10 exons, and encodes reticulum and was purified from human placenta (Hernandez- a protein of 583 amino acids (Reed et al., 2005). Although eight Guzman et al., 2001). It is a monomer with a molecular mass tissue-specific STS transcripts have been identified (Nardi et al., of 63kDa, an N-terminal signal peptide of 21–23 amino acids, 2009), only six are currently included in the gene database: and four potential and two functional (i.e., Asn47, Asn259) isozyme S, and variants X1 to X5 (http://www.ncbi.nlm.nih. glycosylation sites (Reed et al., 2005). Purified STS has been gov/gene). STS transcripts have 235 coding genetic variants crystallized, and its structure has been defined at 2.6-Å resolution (cSNPs) in the db SNP database (http://www.ncbi.nlm.nih.gov/ (pdb code 1P49; Hernandez-Guzman et al., 2001, 2003). The SNP; September 2015), although only one of these cSNPs, three-dimensional structure of STS shows a globular polar Val307Ile, has a minor allele frequency (MAF) >0.01 (0.0172) domain with the catalytic site, and the putative transmembrane (Table 2). SNPs have been reported in the promoter region domain that consists of two antiparallel hydrophobic alpha and in introns and exons of the STS gene (Brookes et al., helices (Hernandez-Guzman et al., 2003) (Figure 2A). STS 2010; Matsumoto et al., 2010, 2013). Seven SNPs have been includes Ca2+ as a cofactor and 10 catalytically important amino identified in the Japanese population, including one SNP in the acid residues: Arg35, Arg36, ARG78, Arg342, Lys134, Lys368, 5′-untranslated region (155G>A), five in the 5′-flanking region, His136, His290, Gln343 and a formylglycine (FGly75). This and one cSNP, Val476Met, with a frequency of 0.014 (Matsumoto posttranslational modification of Cys75 to FGly75 is mediated et al., 2010). For three specific SNPs, functional analysis has by the FGly-generating enzyme encoded by sulfatase-modifying revealed significantly decreased (155A) and increased (−2837A, factor 1 (Preusser-Kunze et al., 2005). −1588C) transcriptional activities in a reporter gene assay in STS catalyzes the hydrolysis of the sulfate moiety in a four-step MCF7 cells, but showed no effects at the protein and DHEAS STS mechanism. According to Ghosh (2007), these steps comprise: activity levels for Val476Met variant (Matsumoto et al., 2013). (1) activation of FGly75 by a water molecule; (2) nucleophilic The loss of STS activity due to STS gene deletion or point attack of hydroxy-FGly on the sulfur atom of the substrate (i.e., mutations results in X-linked ichthyosis, a genetic skin disorder E1-S, DHEA-S), which is facilitated by Ca2+; (3) release of the that affects 1 in 2000 to 1 in 6000 males and is characterized free hydroxy-product (i.e., E1, DHEA); and finally (4) release by typical scaling of the skin epidermis (Gelmetti and Ruggero, − of HSO4 and regeneration of FGly (Figure 2B). As a sulfate 2002). Interestingly, deletions and mutations have been identified moiety covalently linked to hydroxy-FGly has been observed in mainly in the regions from 7 to 10 exon, which encodes the C- the crystal structure of STS, this suggests that the sulfated form of terminal substrate binding part (Gelmetti and Ruggero, 2002). hydroxy-FGly is the resting state for human STS (Ghosh, 2007). This disease results from the inability to liberate cholesterol from Frontiers in Pharmacology | www.frontiersin.org 2 February 2016 | Volume 7 | Article 30 Rižner The Estrone Sulfatase Pathway in Gynecological Diseases FIGURE 3 | Tertiary structure and reaction mechanism of the human SULT1E1 enzyme. (A) Structure of the human SULT1E1 enzyme in complex with PAP and E2 (pdb 4JVL). (B) Reaction mechanism and the roles of catalytical amino-acid residues His107, Lys47, and Ser137. The scheme was adopted from Thomas and Potter (2013). STS is ubiquitously expressed, with its highest protein levels FIGURE 2 | Tertiary structure and reaction mechanism of the human in placenta, and lower levels in breast, skin, liver, lung, ovary, STS enzyme. (A) Structure of the human STS enzyme (pdb 1P49), with adrenal gland, endometrium, brain, and some other tissues. The transmembrane helices and the globular domain with the active site with tissue levels vary across physiological and pathophysiological 2+ cofactor Ca . (B) The reaction mechanism of the STS enzyme and the roles conditions, but our current understanding of the regulation of of the catalytical amino-acid residues His136, Lys134, His290, and Lys368. FGly, formylglycine; HFGly, hydroxyformylglycine; HFGlyS, STS expression is still very limited (Nardi et al., 2009). STS hydroxyformylglycine sulfate. The scheme was adopted from Ghosh (2007). expression is under the control of estrogens in breast cancer (Zaichuk et al., 2007), and it is down-regulated by GnRH agonists (Maitoko and Sasaki, 2004) and danazol
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