Histone acetyltransferases: challenges in targeting bi-substrate enzymes.
Histone acetyltransferases: challenges in targeting bi-substrate enzymes.
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DOI：
10.1186/s13148-016-0225-2
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发表时间：
2016
影响因子：
5.7
通讯作者：
Dekker FJ
中科院分区：
文献类型：
--
作者：
Wapenaar H;Dekker FJ
组蛋白乙酰转移酶（Histone acetyltransferases, HATs）是一种表观遗传酶，它将乙酰基转移到细胞蛋白的赖氨酸残基上，如组蛋白、转录因子、核受体和酶。已经证明，通过组蛋白和非组蛋白的乙酰化，hat在从癌症、炎症性疾病到神经系统疾病等疾病中发挥作用。一些HAT抑制剂，如双底物抑制剂、天然产物衍生物、小分子和蛋白质相互作用抑制剂，已经被开发出来。尽管它们具有潜力，但在体外研究中抑制剂的生物活性与其作为治疗剂的潜在用途之间仍存在很大差距。为了弥补这一差距，需要开发具有改进性能的新型高效HAT抑制剂。然而，在HAT和HAT抑制剂的研究中遇到了一些挑战，这些挑战阻碍了新的HAT抑制剂的开发。hat已被证明在由许多蛋白质组成的复合物中起作用。这些复合物在HATs的活性和靶向特异性中发挥作用，这限制了体外到体内实验的翻译。目前的HAT抑制剂存在一些不理想的特性，如抗氧化活性、反应性、不稳定性、效力低或在HAT亚型和其他酶之间缺乏选择性。HATs的一个特点是它们是双底物酶，催化两种底物之间的反应：辅助因子乙酰辅酶A （Ac-CoA）和含赖氨酸的底物。这对于确定小分子HAT抑制剂的抑制效力和酶抑制实验的可重复性具有重要但经常被忽视的后果。我们设想，仔细表征HAT和HAT抑制剂的分子方面，如HAT催化机制和小分子HAT抑制剂的酶动力学，将极大地促进强效和选择性HAT抑制剂的开发，并为进一步开发治疗剂提供有效的起点。
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.