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Subtype selective substrates for histone deacetylases.

Birgit Heltweg·Franck Dequiedt·Brett L Marshall·Carsten Brauch·Minoru Yoshida·Norikazu Nishino·Eric Verdin·Manfred Jung
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Abstract

To probe the steric requirements for deacylation, we synthesized lysine-derived small molecule substrates and examined structure-reactivity relationships with various histone deacetylases. Rat liver, human HeLa, and human recombinant class I and II histone deacetylases (HDACs) as well as human recombinant NAD(+)-dependent SIRT1 (class III enzyme) were used in these studies. A benzyloxycarbonyl substituent on the alpha-amino group yielded the highest conversion rates. Replacing the epsilon-acetyl group with larger lipophilic acyl substituents led to a pronounced decrease in conversion by class I and II enzymes; the class III enzyme displayed a greater tolerance. Incubations with recombinant FLAG-tagged human HDACs 1, 3, and 6 showed a distinct subtype selectivity among small molecule substrates. The subtype selectivity of HDAC inhibitors could be predicted with these substrates and an easily obtainable mixture of HDAC subtypes.

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AnimalsHeLa CellsHistone DeacetylasesHumansIn Vitro TechniquesLiverLysineRatsRecombinant ProteinsSirtuin 1SirtuinsStereoisomerismStructure-Activity RelationshipSubstrate SpecificityJournal ArticleResearch Support, Non-U.S. Gov't

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Birgit Heltweg, Franck Dequiedt, Brett L Marshall, Carsten Brauch, Minoru Yoshida, Norikazu Nishino, Eric Verdin, Manfred Jung. 2004-10-07. Subtype selective substrates for histone deacetylases.. https://doi.org/10.1021/jm0497592

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