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Histone acetyltransferases: Rising ancient counterparts to protein kinases.

ABSTRACT: Protein kinases catalyze phosphorylation, a posttranslational modification widely utilized in cell signaling. Histone acetyltransferases (HATs) catalyze a counterpart posttranslational modification of acetylation which marks histones for epigenetic signaling but in some cases modifies non-histone proteins to mediate other cellular activities. In addition, recent proteomic studies have revealed that thousands of proteins are acetylated throughout the cell to regulate diverse biological processes, thus placing acetyltransferases on the same playing field as kinases. Emerging biochemical and structural data further supports mechanistic and biological links between the two enzyme families. In this article, we will review what is known to date about the structure, catalysis and mode of regulation of HAT enzymes and draw analogies, where relevant, to protein kinases. This comparison reveals that HATs may be rising ancient counterparts to protein kinases.

SUBMITTER: Yuan H

PROVIDER: S-EPMC4017165 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Histone acetyltransferases: Rising ancient counterparts to protein kinases.

Yuan Hua H Marmorstein Ronen R

Biopolymers 20130201 2

Protein kinases catalyze phosphorylation, a posttranslational modification widely utilized in cell signaling. Histone acetyltransferases (HATs) catalyze a counterpart posttranslational modification of acetylation which marks histones for epigenetic signaling but in some cases modifies non-histone proteins to mediate other cellular activities. In addition, recent proteomic studies have revealed that thousands of proteins are acetylated throughout the cell to regulate diverse biological processes, ...[more]

PMID: 23175385

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Project description:Histone acetyltransferases (HATs) are epigenetic enzymes that install acetyl groups onto lysine residues of cellular proteins such as histones, transcription factors, nuclear receptors, and enzymes. HATs have been shown to play a role in diseases ranging from cancer and inflammatory diseases to neurological disorders, both through acetylations of histone proteins and non-histone proteins. Several HAT inhibitors, like bi-substrate inhibitors, natural product derivatives, small molecules, and protein-protein interaction inhibitors, have been developed. Despite their potential, a large gap remains between the biological activity of inhibitors in in vitro studies and their potential use as therapeutic agents. To bridge this gap, new potent HAT inhibitors with improved properties need to be developed. However, several challenges have been encountered in the investigation of HATs and HAT inhibitors that hinder the development of new HAT inhibitors. HATs have been shown to function in complexes consisting of many proteins. These complexes play a role in the activity and target specificity of HATs, which limits the translation of in vitro to in vivo experiments. The current HAT inhibitors suffer from undesired properties like anti-oxidant activity, reactivity, instability, low potency, or lack of selectivity between HAT subtypes and other enzymes. A characteristic feature of HATs is that they are bi-substrate enzymes that catalyze reactions between two substrates: the cofactor acetyl coenzyme A (Ac-CoA) and a lysine-containing substrate. This has important-but frequently overlooked-consequences for the determination of the inhibitory potency of small molecule HAT inhibitors and the reproducibility of enzyme inhibition experiments. We envision that a careful characterization of molecular aspects of HATs and HAT inhibitors, such as the HAT catalytic mechanism and the enzyme kinetics of small molecule HAT inhibitors, will greatly improve the development of potent and selective HAT inhibitors and provide validated starting points for further development towards therapeutic agents.

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Histone acetyltransferases: Rising ancient counterparts to protein kinases.

Publications

Histone acetyltransferases: Rising ancient counterparts to protein kinases.

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