The Sir2 family of protein deacetylases

The importance of NAD+-dependent deacetylases (Sir2 family or sirtuins) in cell survival, ageing and apoptosis has ignited a flurry of both chemical and cellular investigations aimed at understanding this unique class of enzymes. This review focuses on recent mechanistic advances that highlight structure, catalysis, substrate recognition and interactions with small-molecule effectors. Recent X-ray structures revealed binding sites for both NAD+ and acetyl-peptide. Biochemical studies support a two-step chemical mechanism involving the initial formation of a 1′-O-alkylamidate adduct formed between the acetyl-group and the nicotinamide ribose of NAD+. Acetyl transfer to the 2′ ribose and addition of water yield deacetylated peptide and 2′-O-acetyl-ADP-ribose, a potential second messenger. Also, the molecular basis of nicotinamide inhibition was revealed, and sirtuin activators (resveratrol) and inhibitors (sirtinol and splitomicin) were identified through small-molecule library screening.