Tài liệu Báo cáo khoa học: Small molecule regulation of Sir2 protein deacetylases ppt

MINIREVIEW

Small molecule regulation of Sir2 protein deacetylases

Olivera Grubisha1

, Brian C. Smith2 and John M. Denu1

1 Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI, USA

2 Department of Chemistry, University of Wisconsin, Madison, WI, USA

Introduction

The silent information regulator 2 (Sir2) family of pro￾teins (sirtuins) are class III histone ⁄ protein deacetylases

(HDACs) [1]. Members of this evolutionarily con￾served family include five homologues in yeast (ySir2

and Hst1–4) and seven in humans (SIRT1–7) [2,3],

with key roles in cellular processes such as gene expres￾sion, apoptosis, metabolism and ageing [4]. The found￾ing member, yeast Sir2 (ySir2), was originally

identified as a trans-acting factor involved in transcrip￾tional repression of the silent mating type loci in yeast

[5]. Now it is well established that ySir2 deacetylase

activity is required for silencing at telomeres, rDNA

and the silent mating type loci, and for maintaining

genome integrity [5,6]. In addition to silencing, Sir2

activity is linked to lifespan extension in yeast [7],

worms [8] and flies [9]. SIRT1, the most extensively

studied human Sir2 orthologue, localises to the nucleus

where it negatively regulates damage-responsive Fork￾head transcription factors [10–12] and p53 [13–15],

promoting cell survival under stress. SIRT1 also dis￾plays tissue-specific roles including skeletal muscle

differentiation [16] and fat mobilization in white

adipocytes [17]. In contrast to SIRT1, SIRT2, SIRT3

and SIRT5, no NAD+-dependent protein deacetylase

activity has been reported for SIRT4, SIRT6 and

SIRT7. The possibility remains that SIRT4, 6 and 7

exhibit specificity toward substrates other than those

tested or that these proteins catalyse a distinct reaction.

Keywords

Sir2; deacetylation; sirtuin; NAD; sirtinol;

splitomicin; resveratrol

Correspondence

J. M. Denu, University of Wisconsin,

Department of Biomolecular Chemistry,

1300 University Ave., Madison,

WI 53706–1532, USA

Fax: +1 608 262 5253

Tel: +1 608 265 1859

E-mail: [email protected]

(Received 17 March 2005, revised 6 June

2005, accepted 8 June 2005)

doi:10.1111/j.1742-4658.2005.04862.x

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 acetyl￾ated substrates, which translates into an expanding range of physiological

functions. These roles include control of gene expression, cell cycle regula￾tion, 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+ meta￾bolites 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.

Abbreviations

CR, caloric restriction; ERCs, extrachromosomal rDNA circles; HDAC, histone ⁄ protein deacetylase; NADases, NAD+ glycohydrolases; Npt1,

nicotinate phosphoribosyltransferase; OAADPr, O-acetyl-ADP-ribose; PARPs, poly(ADP-ribose) polymerases; Sir2, silent information regulator 2.

FEBS Journal 272 (2005) 4607–4616 ª 2005 FEBS 4607