组蛋白乙酰转移酶GCN5参与调控代谢性疾病的分子机制

Molecular Mechanism of Histone Acetyltransferase GCN5 in the Regulation of Metabolic Diseases

GCN5是首个在酵母中被克隆和鉴定的组蛋白乙酰转移酶,属于GCN5相关N-乙酰基转移酶超家族成员,具有赖氨酸乙酰转移酶的活性。GCN5主要分布在细胞核内,由可识别组蛋白乙酰基团的溴结构域和具有催化活性的组蛋白乙酰转移酶结构域及N末端结构域组成,其引起的赖氨酸残基的乙酰化修饰能增强组蛋白与DNA的结合力,进而影响基因的转录,参与调控细胞增殖、分化、细胞周期以及DNA损伤/修复等诸多生物进程。近年的研究发现,GCN5可通过对组蛋白及非组蛋白的乙酰化修饰,参与调控肝糖原合成、脂肪生成和成骨细胞分化等。本文重点就GCN5的分子结构、酶活性及其在糖尿病、肥胖、骨质疏松等不同代谢相关疾病中的作用及其分子机制进行综述,对GCN5调控细胞代谢及活性氧生成的机制进行总结,对靶向GCN5的代谢性疾病的治疗前景进行展望。

GCN5,a member of GCN5-related N-acetyltransferase superfamily,is the first histone acetyltransferase cloned and identified in saccharomyces cerevisiae with a main activity of histone acetyltransferase(HAT).GCN5 is mainly distributed in the nucleus and has a catalytic HAT domain,a bromodomain and an N-terminal domain,which likely affects the interactions between histone and DNA and gene transcription by inducing histone acetylation of lysine residues,participates in many biological processes such as cell proliferation,differentiation,cell cycle as well as DNA damage and repair.It has been reported that GCN5 is involved in the regulation of hepatic gluconeogenesis,adipogenesis as well as osteoblast differentiation through acetylation of histone or non-histone proteins.This review focuses on the molecular structure,enzyme activity of GCN5,and discusses the related molecular mechanisms of GCN5 in diabetes,obesity,osteoporosis,cell metabolism,and generation of reactive oxygen species as well as the therapeutic prospect of metabolic diseases targeting GCN5.