Sulfotransferase 2A1 forms estradiol-17-sulfate and celecoxib switches the dominant product from estradiol-3-sulfate to estradiol-17-sulfate

Wang, Liquan; James, Margaret O.

doi:10.1016/j.jsbmb.2005.05.002

Cited by 41 publications

(49 citation statements)

References 49 publications

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“…For assessment of contribution of SULT1A1, SULT1A3, and SULT1E1 in pHLC, the RAF approach was used (Crespi and Miller, 1999;Venkatakrishnan et al, 2000;Grime and Riley, 2006) to account for differences in protein expression. Nitrophenol, dopamine, and estradiol were used as probe substrates to calculate RAFs and were accepted to be selective for the described SULT isoforms (Zhang et al, 1998;Dajani et al, 1999;Wang and James, 2005;Riches et al, 2009). However, some drawbacks such as the involvement of other isoforms at higher substrate concentrations should be considered.…”

Section: Resultsmentioning

confidence: 99%

Investigation on the Enantioselectivity of the Sulfation of the Methylenedioxymethamphetamine Metabolites 3,4-Dihydroxymethamphetamine and 4-Hydroxy-3-Methoxymethamphetamine using the Substrate-Depletion Approach

Schwaninger

Meyer²,

Maurer³

2011

Drug Metab Dispos

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ABSTRACT:Different pharmacokinetic properties are known for the two enantiomers of the entactogen 3,4-methylendioxy-methamphetamine (MDMA), most likely due to enantioselective metabolism. The aim of the present work was 1) the investigation of the main sulfotransferases (SULT) isoenzymes involved in the sulfation of the main MDMA phase I metabolites 3,4-dihydroxymethamphetamine (DHMA) and 4-hydroxy-3-methoxymethamphetamine (HMMA) and 2) the evaluation of a possible enantioselectivity of this phase II metabolic step. Therefore, racemic DHMA and HMMA were incubated with heterologously expressed SULTs, and quantification of the sulfates by liquid chromatography-high-resolution mass spectrometry was conducted. Because separation of DHMA and HMMA sulfate could not be achieved by liquid chromatography, enantioselective kinetic parameters were determined using the substratedepletion approach with enantioselective quantification of substrate consumption by gas chromatography-negative ion chemical ionization mass spectrometry. SULT1A1 and SULT1A3 catalyzed sulfation of DHMA, and SULT1A3 and SULT1E1 catalyzed sulfation of HMMA. SULT1A1 and SULT1E1 revealed classic Michaelis-Menten kinetics, whereas SULT1A3 kinetics showed deviation from the typical Michaelis-Menten kinetics, resulting in a concentrationdependent self-inhibition. SULT1A3 showed the highest affinity and capacity of the SULT isoforms. Marked enantioselectivity could be observed for S-DHMA sulfation by SULT1A3 and in human liver cytosol, whereas no differences were observed for HMMA sulfation. Finally, comparison of K m and V max values calculated using achiral product formation and chiral substrate depletion showed good correlation within 2-fold of each other. In conclusion, preferences for S-enantiomers were observed for DHMA sulfation, but not for HMMA sulfation. IntroductionThe chiral compound R, R,propane-2-amine], also known as ecstasy, is known as a very popular drug of abuse, but it is also associated with damage of serotonergic neurons (Kalant, 2001;Monks et al., 2004;Easton and Marsden, 2006). Metabolism of MDMA may play a role in this neurotoxicity (Miller et al., 1997;Bai et al., 1999;Mueller et al., 2009). As shown in Fig. 1, one major pathway of MDMA includes cytochrome P450 (P450)-catalyzed O-demethylation to 3,4-dihydroxymethamphetamine (DHMA), followed by O-methylation by catechol-O-methyltransferase (COMT) mainly to 4-hydroxy-3-methoxymethamphetamine (HMMA) and conjugation of DHMA and HMMA by sulfotransferases (SULTs) (Maurer, 1996;Maurer et al., 2000;. In urine samples of recreational MDMA users, more than 90% of DHMA and HMMA are excreted as conjugates, with sulfates present in higher concentrations (Shima et al., 2008; A. E. Schwaninger, M. R. Meyer, A. J. Barnes, E. A. Kolbrich-Spargo, D. A. Gorelick, R. S. Goodwin, M. A. Huestis, and H. H. Maurer, manuscript in preparation). For the two enantiomers of MDMA, differences in their dose-response curves and in their in vivo kinetics were observed (Fallon et al., 1999;Kalant, 2001;Kraemer a...

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Section: Resultsmentioning

confidence: 99%

Investigation on the Enantioselectivity of the Sulfation of the Methylenedioxymethamphetamine Metabolites 3,4-Dihydroxymethamphetamine and 4-Hydroxy-3-Methoxymethamphetamine using the Substrate-Depletion Approach

Schwaninger

Meyer²,

Maurer³

2011

Drug Metab Dispos

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“…The technique is expected to translate well to other systems and, in particular, to other SULT isoforms, where SULT1A1 will be used to obtain structures of the binding sites of other putative SULT allosteres, which include the potent inhibition of SULT1A1 by NSAIDs (10, 11); the allosteric regulation of SULT2A1 by celecoxib, an FDA-approved anticancer drug that changes the substrate specificity of the enzyme (49); and the potent inhibition of SULT1E1 by polychlorinated hydroxyl-bisphenols (OH-PCBs)-the putative basis for the endocrine disruptions caused by these environmental toxins (50,51). Beyond using the method in the current study to decipher how, at the molecular level, allosteres control SULT catalytic function lies the important issue of how such insights might be used to deepen our understanding of SULT biology.…”

Section: Discussionmentioning

confidence: 99%

The structure of the catechin-binding site of human sulfotransferase 1A1

Cook

Wang

Girvin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We are just beginning to understand the allosteric regulation of the human cytosolic sulfotransferase (SULTs) family-13 disease-relevant enzymes that regulate the activities of hundreds, if not thousands, of signaling small molecules. SULT1A1, the predominant isoform in adult liver, harbors two noninteracting allosteric sites, each of which binds a different molecular family: the catechins (naturally occurring flavonols) and nonsteroidal antiinflammatory drugs (NSAIDs). Here, we present the structure of an SULT allosteric binding site-the catechin-binding site of SULT1A1 bound to epigallocatechin gallate (EGCG). The allosteric pocket resides in a dynamic region of the protein that enables EGCG to control opening and closure of the enzyme's active-site cap. Furthermore, the structure offers a molecular explanation for the isozyme specificity of EGCG, which is corroborated experimentally. The bindingsite structure was obtained without X-ray crystallography or multidimensional NMR. Instead, a SULT1A1 apoprotein structure was used to guide positioning of a small number of spin-labeled single-Cys mutants that coat the entire enzyme surface with a paramagnetic field of sufficient strength to determine its contribution to the bound ligand's transverse (T 2 ) relaxation from its 1D solution spectrum. EGCG protons were mapped to the protein surface by triangulation using the T 2 values to calculate their distances to a trio of spin-labeled Cys mutants. The final structure was obtained using distance-constrained molecular dynamics docking. This approach, which is readily extensible to other systems, is applicable over a wide range of ligand affinities, requires little protein, avoids the need for isotopically labeled protein, and has no protein molecular weight limitations.sulfotransferase | structure | NMR | allostery | catechin C ytosolic SULTs regulate disease-relevant process in virtually every tissue in the human body (1-5). This small family of broadspecificity enzymes regulates the activities of hundreds, perhaps thousands, of signaling small molecules (e.g., endogenous metabolites, drugs, and other xenobiotics) via regiospecific transfer of the sulfuryl moiety (-SO 3 ) from 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to the hydroxyls and amines of acceptors (1, 6). Sulfonation often radically alters the interactions of a compound with its target and substantially enhances the target's solubility, transport, and clearance (1, 6, 7). Through these and other mechanisms, SULTs contribute in critical ways to maintaining signaling homeostasis and neutralizing toxins (6,8).Given their wide-ranging roles in regulating cellular processes, it is perhaps expected that SULTs would have evolved means of communicating with their environments-mechanisms that enable them to read and respond to the small-molecule composition of their "milieu." Early screening studies intimated that SULTs might be subject to small-molecule allosteric control (9, 10), and recent work confirms this (11). SULT1A1, the most abundant isoform in adult h...

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“…The most important pathway involves in the formation of estrogen is sulfatase pathway which involves conversion of inactive estrone sulfate into active estrone (Wang et al, 2005). Sulfotransferases (SULT) sulfonate estrone to inactive estrone sulfate, whereas steroid sulfatase (STS) hydrolyzes estrone sulfate to estrone.…”

Section: Discussionmentioning

confidence: 99%