Sirtuins: NAD+-dependent deacetylase mechanism and regulation

Sirtuins are NAD(+)-dependent deacetylases involved in chemical reversal of acetyllysine modifications of cellular proteins. Deacetylation catalyzed by sirtuins is implicated in regulating diverse biological processes, including energy homeostasis. The mechanism of NAD(+)-dependent deacetylation is proposed to occur via an ADPR-peptidyl-imidate intermediate, resulting from reaction of NAD(+) and an acetyllysine residue. This mechanism enables sirtuins to respond dynamically to intracellular fluctuations of NAD(+) and nicotinamide. Chemical probes such as nicotinamide antagonists and thioacetyl compounds provide key support for the imidate mechanism of sirtuin deacetylation catalysis. Novel new directions include chemical probes to study sirtuins in cells, and the discovery of novel post-translational modifications besides acetyl, such as succinyl and malonyl, that are regulated by sirtuins.