title: Mechanism-based modulator discovery for sirtuin-catalyzed deacetylation reaction.
abstract: Silent information regulator 2 (Sir2) enzymes or sirtuins are a family of evolutionarily conserved intracellular protein deacetylases that can catalyze the acetyl group removal from the specific Nε-acetyl-lysine (AcK) side chains on a variety of proteins from all kingdoms of life. Yeast Sir2 was the first sirtuin identified, and so far seven sirtuins (i.e. SIRT1-7) have been found in mammals including humans. The sirtuin-catalyzed deacetylation reaction has captured tremendous interest during the past a few years because of (i) its increasingly demonstrated importance in many crucial biological processes such as gene transcription, metabolism, and aging, and thus its therapeutic potential for metabolic and age-related diseases and cancer, and (ii) its unique deacetylation chemistry. Specifically, the sirtuin-catalyzed AcK side chain deacetylation is not merely an amide hydrolysis reaction, instead is coupled to the nicotinamide cleavage from β-nicotinamide adenine dinucleotide (β-NAD+ or NAD+) with the generation of three enzymatic products, i.e. the deacetylated protein species, nicotinamide, and 2'-O-acetyl-ADP-ribose (2'-O-AADPR). Here the author would like to review the past endeavors on developing mechanism-based sirtuin modulators (inhibitors and activators). The first part of this article will provide an updated mechanistic picture of the sirtuin-catalyzed deacetylation reaction. The second part will be focused on how the mechanistic knowledge has been exploited for the design of effective sirtuin modulators.
authors.affiliation: School of Pharmacy, Jiangsu University, Zhenjiang 212013, P R China. wzheng@ujs.edu.cn
authors.forename: Weiping
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000595:Amino Acid Sequence; D055162:Biocatalysis / Q000187:drug effects*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008969:Molecular Sequence Data; D037761:Sirtuins / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D037761:Sirtuins