Reference : Subtype Selective Substrates For Histone Deacetylases
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Subtype Selective Substrates For Histone Deacetylases
Heltweg, B. [> > > >]
Dequiedt, Franck mailto [Université de Liège - ULiège > > GIGA-Research >]
Marshall, Bl. [> > > >]
Branch, C. [> > > >]
Yoshida, M. [> > > >]
Nishino, N. [> > > >]
Verdin, Emeline mailto [Université de Liège - ULiège > > Génie chimique - Opérations physiques unitaires >]
Jung, M. [> > > >]
Journal of Medicinal Chemistry
Yes (verified by ORBi)
[en] 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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