Stimulation of histone deacetylase activity by metabolites of intermediary metabolism

J Biol Chem. 2012 Sep 14;287(38):32006-16. doi: 10.1074/jbc.M112.362467. Epub 2012 Jul 20.

Abstract

Histone deacetylases (HDACs) function in a wide range of molecular processes, including gene expression, and are of significant interest as therapeutic targets. Although their native complexes, subcellular localization, and recruitment mechanisms to chromatin have been extensively studied, much less is known about whether the enzymatic activity of non-sirtuin HDACs can be regulated by natural metabolites. Here, we show that several coenzyme A (CoA) derivatives, such as acetyl-CoA, butyryl-CoA, HMG-CoA, and malonyl-CoA, as well as NADPH but not NADP(+), NADH, or NAD(+), act as allosteric activators of recombinant HDAC1 and HDAC2 in vitro following a mixed activation kinetic. In contrast, free CoA, like unconjugated butyrate, inhibits HDAC activity in vitro. Analysis of a large number of engineered HDAC1 mutants suggests that the HDAC activity can potentially be decoupled from "activatability" by the CoA derivatives. In vivo, pharmacological inhibition of glucose-6-phosphate dehydrogenase (G6PD) to decrease NADPH levels led to significant increases in global levels of histone H3 and H4 acetylation. The similarity in structures of the identified metabolites and the exquisite selectivity of NADPH over NADP(+), NADH, and NAD(+) as an HDAC activator reveal a previously unrecognized biochemical feature of the HDAC proteins with important consequences for regulation of histone acetylation as well as the development of more specific and potent HDAC inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Animals
  • Cell Nucleus / metabolism
  • Chromatin / chemistry
  • Coenzyme A / chemistry
  • Epigenesis, Genetic
  • Gene Expression Regulation, Enzymologic*
  • HeLa Cells
  • Histone Deacetylase 1 / antagonists & inhibitors
  • Histone Deacetylase 1 / metabolism*
  • Histone Deacetylases / metabolism*
  • Histones / metabolism
  • Humans
  • Insecta
  • Kinetics
  • Mutation
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Sirtuins / chemistry*
  • Subcellular Fractions / metabolism

Substances

  • Chromatin
  • Histones
  • Recombinant Proteins
  • Sirtuins
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylases
  • Coenzyme A