Biochemistry and Enzymology of Sirtuins

Abstract

Sirtuins are enzymes that utilize NAD+ as a substrate to effect deacetylation and deacylations of cellular protein substrates. The prototypical reaction characterized for these enzymes is protein lysine N-(epsilon)-deacetylation, which also produces nicotinamide and a novel compound called 2′-O-acetyl-ADPR as co-products. This reaction is catalyzed by an active site that is highly conserved across evolutionary time, and this reaction has been observed for sirtuins encoded by genomes as diverse as mycobacteria, archaea, protozoa as well as humans. The human sirtuin repertoire includes seven isoforms, named SIRT1-7, which have different cellular localizations and cellular functions. These sirtuins have high sequence similarity, particularly in their catalytic domain, but appear to have diversified functions as deacetylases and deacylases. This review broadly considers the catalytic properties of these enzymes and how they are regulated in cells. In particular, emphasis is given to mechanisms that alter sirtuin levels and activities in mammalian cells. Several sirtuin assays are also discussed. This chapter provides a broad overview of the enzymology and biological properties of this enzyme family.