Mechanism-based Modulator Discovery for Sirtuin-catalyzed Deacetylation Reaction

作者：Zheng Weiping^*

来源：Mini Reviews in Medicinal Chemistry, 2013, 13(1): 132-154.

• Activator
• Inhibitor
• Mechanism
• Mechanism-based
• Protein deacetylase
• Sirtuin

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 N-epsilon-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 beta-nicotinamide adenine dinucleotide (beta-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.

• 出版日期2013-1
• 单位江苏大学