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Research ArticleArticle

The Allosteric Binding Sites of Sulfotransferase 1A1

Ian Cook, Ting Wang, Charles N. Falany and Thomas S. Leyh
Drug Metabolism and Disposition March 2015, 43 (3) 418-423; DOI: https://doi.org/10.1124/dmd.114.061887
Ian Cook
Department of Microbiology and Immunology (I.C., T.W., T.S.L.), Albert Einstein College of Medicine, Bronx, New York; and Department of Pharmacology and Toxicology, University of Alabama School of Medicine at Birmingham, Birmingham, Alabama (C.N.F.)
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Ting Wang
Department of Microbiology and Immunology (I.C., T.W., T.S.L.), Albert Einstein College of Medicine, Bronx, New York; and Department of Pharmacology and Toxicology, University of Alabama School of Medicine at Birmingham, Birmingham, Alabama (C.N.F.)
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Charles N. Falany
Department of Microbiology and Immunology (I.C., T.W., T.S.L.), Albert Einstein College of Medicine, Bronx, New York; and Department of Pharmacology and Toxicology, University of Alabama School of Medicine at Birmingham, Birmingham, Alabama (C.N.F.)
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Thomas S. Leyh
Department of Microbiology and Immunology (I.C., T.W., T.S.L.), Albert Einstein College of Medicine, Bronx, New York; and Department of Pharmacology and Toxicology, University of Alabama School of Medicine at Birmingham, Birmingham, Alabama (C.N.F.)
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Abstract

Human sulfotransferases (SULTs) comprise a small, 13-member enzyme family that regulates the activities of thousands of compounds—endogenous metabolites, drugs, and other xenobiotics. SULTs transfer the sulfuryl-moiety (–SO3) from a nucleotide donor, PAPS (3′-phosphoadenosine 5′-phosphosulfate), to the hydroxyls and primary amines of acceptors. SULT1A1, a progenitor of the family, has evolved to sulfonate compounds that are remarkably structurally diverse. SULT1A1, which is found in many tissues, is the predominant SULT in liver, where it is a major component of phase II metabolism. Early work demonstrated that catechins and nonsteroidal anti-inflammatory drugs inhibit SULT1A1 and suggested that the inhibition was not competitive versus substrates. Here, the mechanism of inhibition of a single, high affinity representative from each class [epigallocatechin gallate (EGCG) and mefenamic acid] is determined using initial-rate and equilibrium-binding studies. The findings reveal that the inhibitors bind at sites separate from those of substrates, and at saturation turnover of the enzyme is reduced to a nonzero value. Further, the EGCG inhibition patterns suggest a molecular explanation for its isozyme specificity. Remarkably, the inhibitors bind at sites that are separate from one another, and binding at one site does not affect affinity at the other. For the first time, it is clear that SULT1A1 is allosterically regulated, and that it contains at least two, functionally distinct allosteric sites, each of which responds to a different class of compounds.

Footnotes

    • Received November 5, 2014.
    • Accepted December 22, 2014.
  • The work was supported by the National Institutes of Health [Grants GM38953 and GM106158].

  • dx.doi.org/10.1124/dmd.114.061887.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (3)
Drug Metabolism and Disposition
Vol. 43, Issue 3
1 Mar 2015
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Research ArticleArticle

SULT1A1 Allosteric Binding Sites

Ian Cook, Ting Wang, Charles N. Falany and Thomas S. Leyh
Drug Metabolism and Disposition March 1, 2015, 43 (3) 418-423; DOI: https://doi.org/10.1124/dmd.114.061887

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Research ArticleArticle

SULT1A1 Allosteric Binding Sites

Ian Cook, Ting Wang, Charles N. Falany and Thomas S. Leyh
Drug Metabolism and Disposition March 1, 2015, 43 (3) 418-423; DOI: https://doi.org/10.1124/dmd.114.061887
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