Sulfotransferase 1A1 Substrate Selectivity: A Molecular Clamp Mechanism

Biochemistry
Ian T CookT S Leyh

Abstract

The human cytosolic sulfotransferases (SULTs) regulate hundreds, perhaps thousands, of small molecule metabolites and xenobiotics via transfer of a sulfuryl moiety (-SO3) from PAPS (3'-phosphoadenosine 5'-phosphosulfate) to the hydroxyls and primary amines of the recipients. In liver, where it is abundant, SULT1A1 engages in modifying metabolites and neutralizing toxins. The specificity of 1A1 is the broadest of any SULT, and understanding its selectivity is fundamental to understanding its biology. Here, for the first time, we show that SULT1A1 substrates separate naturally into two classes: those whose affinities are either enhanced ∼20-fold (positive synergy) or unaffected (neutral synergy) by the presence of a saturating nucleotide. kcat for the positive-synergy substrates is shown to be ∼100-fold greater than that of neutral-synergy compounds; consequently, the catalytic efficiency (kcat/Km) is approximately 3 orders of magnitude greater for the positive-synergy species. All-atom dynamics modeling suggests a molecular mechanism for these observations in which the binding of only positive-synergy compounds causes two phenylalanine residues (F81 and 84) to reposition and "sandwich" the phenolic moiety of the substrates, thus...Continue Reading

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Citations

Jun 30, 2016·Biochemistry·Ting WangThomas S Leyh
Jan 14, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Zachary E TibbsCharles N Falany
Dec 15, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ting WangThomas S Leyh
Dec 3, 2016·Proceedings of the National Academy of Sciences of the United States of America·Ian CookThomas S Leyh
May 31, 2018·The Journal of Clinical Endocrinology and Metabolism·Sonia García-CalzónCharlotte Ling
Nov 5, 2017·Nature Communications·Carmela GalloAngelo Fontana
Nov 20, 2020·The Journal of Biological Chemistry·Ian CookThomas S Leyh
Feb 2, 2021·The Journal of Biological Chemistry·Ting WangThomas S Leyh
Jan 24, 2021·The Journal of Biological Chemistry·Ian CookThomas S Leyh
May 9, 2018·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Fei ShenWei Li

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