Sirtuins: NAD+-dependent deacetylase mechanism and regulation

► Sirtuin NAD+-dependent deacetylation proceeds via a novel enzymatic mechanism. ► Deacetylation via an ADPR-imidate enables regulation by NAD+ and nicotinamide. ► Chemical probes of sirtuins have increased understanding of the imidate mechanism. ► Lysine acyl modifications beyond acetylation are deacylated by select sirtuins.