Abstract
Sir2 enzymes are broadly conserved from bacteria to humans, and eukaryotic organisms typically contain multiple Sir2 enzymes that target different protein substrates to mediate diverse biological processes including gene silencing, DNA repair, genome stability, longevity, metabolism, adipogenesis, and cell physiology. These enzymes use a conserved catalytic core domain to bind NAD+ and acetyl-lysine-bearing protein targets. They generate lysine, 2′-0-acetyl-ADP-ribose, and nicotinamide products and contain more variable N- and C-terminal domains that may contribute protein-specific functions. Structural and related biochemical studies on the Sir2 enzymes from several laboratories have provided important insights into their conserved mode of NAD+ and acetyl-lysine binding, recognition, and catalysis, as well as the distinguishing features that allow different members of the family to target their respective cognate substrates. This chapter summarizes the results of the structural analysis of the Sir2 enzymes as well as the implications of these studies for structure-based design of Sir2-specific small-molecule compounds that might modulate Sir2 functions for therapeutic application.
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References
Guarente L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev 2000;14:1021–1026.
Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature, 2000;403:795–800.
de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003;370:737–749.
Sauve AA, Celic I, Avalos J, Deng H, Boek JD, Schramm VL. Chemistry of gene silencing: the mechanism of NAD+-dependent deacetylation reactions. Biochemistry 2001;40:15,456–15,463.
Jackson MD, Denu JM. Structural identification of 2′-and 3′-O-acetyl-ADP-ribose as novel metabolites derived from the Sir2 family of beta-NAD+-dependent histone/protein deacetylases. J Biol Chem 2002;277:18,535–18,544.
Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair D. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast Sir2 and human SIRT1. J Biol Chem 2002;277:45,099–45,107.
Buck SW, Gallo CM, Smith JS. Diversity in the Sir2 family of protein deacetylases. J Leukoc Biol 2004;75:939–950.
Luo J, Nikolaer AY, Imai S. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 2001;107:137–148.
Vaziri H, Dessain SK, Ng Eaton E, et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 2001;107:149–159.
Brunet A, Sweeneg LB, Sturgill JF, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004;303:2011–2015.
Motta MC, Divecha N, Lemieu XM, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell 2004;116:551–563.
Daitoku H, Natta M, Matsuzaki H, et al. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad SciUSA 2004;101:10,042–10,047.
Picard F, Kurtev M, Chung N, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 2004;429:771–776.
North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is a NAD+-dependent tubulin deacetylase. Mol Cell 2003;11:437–444.
Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 2000; 289:2126–2128.
Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 2001;410:227–230.
Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003;425:191–196.
Wood JG, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004;430:686–689.
Finnin MS, Donigian JR, Pavletich NP. Structure of the histone deacetylase SIRT2. Nat Struct Biol 2001;8:621–625.
Zhao K, Chai X, Clements A, Marmorstein R. Structure and autoregulation of the yeast Hst2 homolog of Sir2. Nat Struct Biol 2003; 10:864–871.
Avalos JL, Boeke JD, Wolberger C. Structural basis for the mechanism and regulation of Sir2 enzymes. Mol Cell 2004;13:639–648.
Avalos JL, Celic I, Muhammad S, Cosgrove MS, Boeke JD, Wolberger C. Structure of a Sir2 enzyme bound to an acetylated p53 peptide. Mol Cell 2002;10:523–535.
Zhao K, Chai X, Marmorstein R. Structure and substrate binding properties of cobB, a Sir2 homolog protein deacetylase from Escherichia coli. J Mol Biol 2004;337:731–741.
Min J, Landry J, Sternglanz R. Crystal structure of a SIR2 homolog-NAD complex. Cell 2001;105:269–279.
Jacobs SA, Harp JM, Devarakonda S, Kim Y, Rastinejad F, Khorasanizadeh S. The active site of the SET domain is constructed on a knot. Nat Struct Biol 2002;9:833–838.
Chang JH, Kim HC, Hwang KY, et al. Structural basis for the NAD-dependent deacetylase mechanism of Sir2. J Biol Chem 2002;277:34,489–34,498.
Zhao K, Chai X, Marmorstein R. Structure of the yeast Hst2 protein deacetylase in ternary complex with 2′-O-acetyl ADP ribose and histone peptide. Structure 2003;11:1403–1411.
Zhao K, Narshaw R, Chai X, Marmorstein R. Structural basis for nicotinamide cleavage and ADP-ribose transfer by NAD+-dependent Sir2 histone/protein deacetylases. Proc Natl Acad Sci U S A 2004;101:8563–8568.
Starai VJ, Celic I, Cole RN, Boeke JD, Escalante-Semerena JC. Sir2-dependent activation of acetyl-CoA synthetase by deacetylation of active lysine. Science 2002;298:2390–2392.
Sauve AA, Schramm VL. Sir2 regulation by nicotinamide results from switching between base exchange and deacetylation chemistry. Biochemistry 2003; 42:9249–9256.
Grozinger CM, Chao ED, Blackwell HE, Mozed D, Schreiber SL. Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J Biol Chem 2001;276:38,837–38,843.
Bedalov A, Gatbonton T, Irvine WP, Gottschling DE, Simon JA. Identification of a small molecule inhibitor of Sir2p. Proc Natl Acad Sci U S A 2001;98:15,113–15,118.
Jackson MD, Schmidt MT, Oppenheimer NJ, Denu JM. Mechanism of nicotinamide inhibition and transglycosidation by Sir2 histone/protein deacetylases. J Biol Chem 2003;278:50,985–50,998.
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© 2006 Humana Press Inc., Totowa, NJ
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Zhao, K., Marmorstein, R. (2006). Structure of the Sir2 Family of NAD+-Dependent Histone/Protein Deacetylases. In: Verdin, E. (eds) Histone Deacetylases. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59745-024-3:203
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DOI: https://doi.org/10.1385/1-59745-024-3:203
Publisher Name: Humana Press
Print ISBN: 978-1-58829-499-9
Online ISBN: 978-1-59745-024-9
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