The sirtuin proteins are broadly conserved NAD+-dependant protein deacetylases, or in some cases ADP-ribotransferases, that are implicated in diverse biological processes including DNA regulation, metabolism and longevity. In mammals, sirtuins regulate transcription factors such as p53, FOXO, and PPARγ to counteract age associated diseases such as obesity, and type II diabetes, thus pointing to these enzymes as important drug targets. Deacetylation by Sir2 enzymes proceeds by a novel reaction in which the substrates NAD+ and acetyl-lysine within protein targets are used to generate lysine, 2'-O-acetyl-ADP-ribose, and nicotinamide products. Nicotinamide is also a non-competitive inhibitor of the reaction by binding to a reaction intermediate to reform the NAD+ substrate. In my seminar I will describe the studies from my laboratory using the yeast Hst2 member of this protein family as a model to understand the structure and chemistry of how the sirtuin enzymes catalyze NAD+-dependant deacetylation and how these enzymes are inhibited by nicotinamide. Implications of these studies for the rational design of sirtuin-specific effectors will also be discussed.