Biology, Chemistry, and Pharmacology of Sirtuins.

Sirtuins are a family of protein deacylases related by amino acid sequence and cellular function to the yeast Saccharomyces cerevisiae protein Sir2 (Silent Information Regulator-2), the first of this class of enzymes to be identified and studied in detail. Based on its initially discovered activity, Sir2 was classified as a histone deacetylase that removes acetyl groups from histones H3 and H4. The acetylation/deacetylation of these particular substrates leads to changes in transcriptional silencing at specific loci in the yeast genome, hence its name. Sirtuins, however, have been shown to regulate a wide variety of cellular processes beyond transcriptional repression in varied subcellular compartments and in different cell types. Mechanistically distinct from Zn(2+)-dependent deacylases, sirtuins use nicotinamide adenine dinucleotide as a cofactor in the removal of acetyl and other acyl groups linking metabolic status and posttranslational modification. Sirtuins' unique position has made them attractive targets for small-molecule drug development. In this chapter, we describe the biological roles, therapeutic areas in which sirtuins may play a role and development of small-molecule inhibitors of sirtuins employing phenotypic screening technologies ranging from assays in yeast, as well as biochemical screens to yield lead drug development candidates targeting a broad spectrum of human diseases.