Small molecule regulation of Sir2 protein deacetylases

被引:120
|
作者
Grubisha, O
Smith, BC
Denu, JM
机构
[1] Univ Wisconsin, Dept Biomol Chem, Madison, WI 53706 USA
[2] Univ Wisconsin, Dept Chem, Madison, WI 53706 USA
关键词
Sir2; deacetylation; sirtuin; NAD; sirtinol; splitomicin; resveratrol;
D O I
10.1111/j.1742-4658.2005.04862.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The Sir2 family of histone/protein deacetylases (sirtuins) is comprised of homologues found across all kingdoms of life. These enzymes catalyse a unique reaction in which NAD(+) and acetylated substrate are converted into deacetylated product, nicotinamide, and a novel metabolite O-acetyl ADP-ribose. Although the catalytic mechanism is well conserved across Sir2 family members, sirtuins display differential specificity toward acetylated substrates, which translates into an expanding range of physiological functions. These roles include control of gene expression, cell cycle regulation, apoptosis, metabolism and ageing. The dependence of sirtuin activity on NAD(+) has spearheaded investigations into how these enzymes respond to metabolic signals, such as caloric restriction. In addition, NAD(+) metabolites and NAD(+) salvage pathway enzymes regulate sirtuin activity, supporting a link between deacetylation of target proteins and metabolic pathways. Apart from physiological regulators, forward chemical genetics and high-throughput activity screening has been used to identify sirtuin inhibitors and activators. This review focuses on small molecule regulators that control the activity and functions of this unusual family of protein deacetylases.
引用
收藏
页码:4607 / 4616
页数:10
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