title: Biology, Chemistry, and Pharmacology of Sirtuins.
abstract: 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.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
authors.forename: A
authors.initials: A
authors.lastname: Bedalov
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
authors.forename: S
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, United States. Electronic address: jsimon@fhcrc.org.
authors.forename: J A
authors.initials: JA
authors.lastname: Simon
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D055808:Drug Discovery / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008659:Metabolic Diseases / Q000188:drug therapy / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D054852:Small Molecule Libraries; D009243:NAD; D037761:Sirtuins
keywords: Acetylation; Aging; Cancer; Deacetylase; Epigenetic; Inhibitor; Metabolism; Mitochondria; Sirtuin; Transcription