Sir2 regulation and chemical modulation

Summary

Principal Investigator: Anthony Sauve
Abstract: The objective of the proposed research is to deduce mechanistic and regulatory principles that control the activities of sirtuin enzymes in yeast and human cells. These principles will be used to design small molecules that can activate sirtuins in cells. Sirtuins regulate a host of biologically significant activities including stress resistance, gene silencing and longevity. Sirtuins are implicated in mediating biological effects associated with calorie restriction. Calorie restriction has been shown to have numerous positive health benefits in mammals including reduced adipogenesis, insulin sensitivity and increased lifespan. These biological effects have raised interest in the enzymatic mechanisms of sirtuins, the means by which they are regulated in cells and the ways in which they might be modulated pharmacologically for improved human health. Sirtuins are NAD dependent deacetylases that remove acetyl-groups of acetyllysine modified histones and transcription factors thereby regulating chromatin and gene expression. We and others have demonstrated that these actvitities are regulated by NAD and nicotinamide levels in cells, and that the sirtuins are able to integrate information from energy and metabolic states to control genetic events. As part of our goal to better understand the functions of these enzymes and how they can be modulated in cells we propose to investigate the following specific aims: In Aim1 we propose to characterize the biochemical functions of this unique class of enzymes, emphasizing their chemical novelty and the incorporation of NAD in deacetylation reactions. In Aim2 we propose to show how enzymatic activity provides a mechanism for nicotinamide regulation of sirtuin activity. In addition with a recently developed mass spectrometry method we hope to gain new insights into how nicotinamide regulates sirtuins in cells. In Aim 3 we explore the development of small molecule activators of sirtuins designed from knowledge of the sirtuin reaction mechanism and the mechanism of nicotinamide regulation. These activators embody a novel approach to upregulate sirtuin action in cells and provide a potential entrypoint for pharmacological intervention to increase cell stress resistance and cell survival. Achievement of these aims is expected to provide new insights into the biochemistry and regulation of these enzymes, and provide proof of concept for new therapeutics that can activate sirtuins to treat diabetes and degenerative disorders.
Funding Period: ----------------2009 - ---------------2010-
more information: NIH RePORT

Top Publications

  1. ncbi SIRT1 and endocrine signaling
    Tianle Yang
    Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, LC 216, New York, NY 10021, USA
    Trends Endocrinol Metab 17:186-91. 2006
  2. pmc Characterization of nicotinamidases: steady state kinetic parameters, classwide inhibition by nicotinaldehydes, and catalytic mechanism
    Jarrod B French
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States
    Biochemistry 49:10421-39. 2010
  3. pmc Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes
    Carles Canto
    Nestlé Institute of Health Sciences, Lausanne CH 1015, Switzerland
    Mol Aspects Med 34:1168-201. 2013
  4. pmc Plasmodium falciparum Sir2 is an NAD+-dependent deacetylase and an acetyllysine-dependent and acetyllysine-independent NAD+ glycohydrolase
    Jarrod B French
    Department of Pharmacology, Weill Cornell College of Medicine, 1300 York Avenue LC216, New York, New York 10065, USA
    Biochemistry 47:10227-39. 2008
  5. ncbi NAD+ and vitamin B3: from metabolism to therapies
    Anthony A Sauve
    Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA
    J Pharmacol Exp Ther 324:883-93. 2008
  6. ncbi Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells
    Tianle Yang
    Department of Pharmacology, Weill Medical College of Cornell University, Manhattan, NY 10021, USA
    J Med Chem 50:6458-61. 2007
  7. pmc Nicotinamide riboside kinase structures reveal new pathways to NAD+
    Wolfram Tempel
    Structural Genomics Consortium and Department of Pharmacology, University of Toronto, Toronto, Canada
    PLoS Biol 5:e263. 2007
  8. pmc Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival
    Hongying Yang
    Department of Pathology, Paul F Glenn Laboratories, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Cell 130:1095-107. 2007
  9. pmc NAD metabolism and sirtuins: metabolic regulation of protein deacetylation in stress and toxicity
    Tianle Yang
    Department of Pharmacology, Weill Medical College of Cornell University, New York, NY, USA
    AAPS J 8:E632-43. 2006
  10. pmc PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation
    Peter Bai
    Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Universite de Strasbourg, ESBS, Illkirch, France
    Cell Metab 13:461-8. 2011

Scientific Experts

  • Anthony Sauve
  • Yana Cen
  • Tianle Yang
  • Peter Bai
  • Carles Canto
  • Jarrod B French
  • Borbala Kiss
  • Hiroyasu Yamamoto
  • Aline Huber
  • Attila Brunyánszki
  • Johan Auwerx
  • Valerie Schreiber
  • Hugues Oudart
  • Josiane Menissier-de Murcia
  • Dou Yeon Youn
  • Ping Xu
  • Silvia Diani-Moore
  • Tong Zhang
  • Hongying Yang
  • Wolfram Tempel
  • Jessica N Falco
  • Pal Gergely
  • Charles Thomas
  • Sander M Houten
  • Riekelt H Houtkooper
  • Magdolna Szántó
  • Kristina Schoonjans
  • Arleen B Rifkind
  • Xintian Li
  • Tracy L Vrablik
  • Prosenjit Mondal
  • Eleanor Allen
  • Payal Ram
  • Wendy Hanna-Rose
  • W Lee Kraus
  • Raga Krishnakumar
  • Matthew J Gamble
  • Kristine M Frizzell
  • Michelle E DuMond
  • Jhoanna G Berrocal
  • Charles Brenner
  • Peter Belenky
  • Joseph A Baur
  • Anthony Rosenzweig
  • Vilhelm A Bohr
  • Takashi Matsui
  • Juan J Carmona
  • Noel Yan Ki Chan
  • David A Sinclair
  • Wael M Rabeh
  • Nadja C Souza-Pinto
  • Rafael De Cabo
  • Dudley W Lamming
  • Lyudmila Nedyalkova
  • Marzena Wojcik
  • Evelyn Perez
  • Heather F Seidle
  • Katrina L Bogan
  • Hee Won Park
  • Maofu Fu
  • Richard Pestell

Detail Information

Publications17

  1. ncbi SIRT1 and endocrine signaling
    Tianle Yang
    Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, LC 216, New York, NY 10021, USA
    Trends Endocrinol Metab 17:186-91. 2006
    ....
  2. pmc Characterization of nicotinamidases: steady state kinetic parameters, classwide inhibition by nicotinaldehydes, and catalytic mechanism
    Jarrod B French
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States
    Biochemistry 49:10421-39. 2010
    ..pneumoniae enzyme involving key catalytic residues, a catalytic transition metal ion, and the intermediacy of a thioester intermediate...
  3. pmc Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes
    Carles Canto
    Nestlé Institute of Health Sciences, Lausanne CH 1015, Switzerland
    Mol Aspects Med 34:1168-201. 2013
    ..Finally, we give an overview of the possibilities of pharmacological intervention to modulate PARP and SIRT enzymes either directly, or through modulating NAD(+) homeostasis. ..
  4. pmc Plasmodium falciparum Sir2 is an NAD+-dependent deacetylase and an acetyllysine-dependent and acetyllysine-independent NAD+ glycohydrolase
    Jarrod B French
    Department of Pharmacology, Weill Cornell College of Medicine, 1300 York Avenue LC216, New York, New York 10065, USA
    Biochemistry 47:10227-39. 2008
    ..These findings also illustrate the potential utility of nicotinamide as a probe for mechanisms of sirtuin-catalyzed ADP-ribosyl transfer...
  5. ncbi NAD+ and vitamin B3: from metabolism to therapies
    Anthony A Sauve
    Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA
    J Pharmacol Exp Ther 324:883-93. 2008
    ....
  6. ncbi Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells
    Tianle Yang
    Department of Pharmacology, Weill Medical College of Cornell University, Manhattan, NY 10021, USA
    J Med Chem 50:6458-61. 2007
    ..2-2.7-fold in several mammalian cell lines. These findings establish bioavailability and potent effects of these nucleosides in stimulating the increase of NAD+ concentrations in mammalian cells...
  7. pmc Nicotinamide riboside kinase structures reveal new pathways to NAD+
    Wolfram Tempel
    Structural Genomics Consortium and Department of Pharmacology, University of Toronto, Toronto, Canada
    PLoS Biol 5:e263. 2007
    ..Additionally, nicotinic acid riboside is utilized in vivo by Urh1, Pnp1, and Preiss-Handler salvage. Thus, crystal structures of Nrk1 led to the identification of new pathways to NAD+...
  8. pmc Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival
    Hongying Yang
    Department of Pathology, Paul F Glenn Laboratories, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Cell 130:1095-107. 2007
    ..We discuss the relevance of these findings to understanding how nutrition modulates physiology and to the evolution of apoptosis...
  9. pmc NAD metabolism and sirtuins: metabolic regulation of protein deacetylation in stress and toxicity
    Tianle Yang
    Department of Pharmacology, Weill Medical College of Cornell University, New York, NY, USA
    AAPS J 8:E632-43. 2006
    ....
  10. pmc PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation
    Peter Bai
    Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Universite de Strasbourg, ESBS, Illkirch, France
    Cell Metab 13:461-8. 2011
    ..These data show how PARP-1 inhibition has strong metabolic implications through the modulation of SIRT1 activity, a property that could be useful in the management not only of metabolic diseases, but also of cancer...
  11. pmc PARP-2 regulates SIRT1 expression and whole-body energy expenditure
    Peter Bai
    Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Universite de Strasbourg, ESBS, 67412 Illkirch, France
    Cell Metab 13:450-60. 2011
    ....
  12. pmc Mechanism-based affinity capture of sirtuins
    Yana Cen
    Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
    Org Biomol Chem 9:987-93. 2011
    ..Finally, we demonstrate the ability to simultaneously detect multiple sirtuin isoforms in reaction mixtures with this methodology, establishing proof of concept tools for chemical studies of sirtuins in complex biological samples...
  13. pmc Identification of the aryl hydrocarbon receptor target gene TiPARP as a mediator of suppression of hepatic gluconeogenesis by 2,3,7,8-tetrachlorodibenzo-p-dioxin and of nicotinamide as a corrective agent for this effect
    Silvia Diani-Moore
    Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10065, USA
    J Biol Chem 285:38801-10. 2010
    ..The results reveal that TiPARP can mediate a TCDD effect, that the AHR is linked to PGC1α function and stability and that NAM has novel AHR antagonist activity...
  14. pmc Transition state of ADP-ribosylation of acetyllysine catalyzed by Archaeoglobus fulgidus Sir2 determined by kinetic isotope effects and computational approaches
    Yana Cen
    Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 132:12286-98. 2010
    ..A concerted yet highly asynchronous substitution mechanism forms the ADPR-peptidylimidate intermediate of the sirtuin deacetylation reaction...
  15. pmc Sirtuin chemical mechanisms
    Anthony A Sauve
    Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10065, USA
    Biochim Biophys Acta 1804:1591-603. 2010
    ..This review broadly surveys the chemistries and chemical mechanisms of these enzymes...
  16. pmc Enzymes in the NAD+ salvage pathway regulate SIRT1 activity at target gene promoters
    Tong Zhang
    Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA
    J Biol Chem 284:20408-17. 2009
    ..This mechanism, in collaboration with NAMPT-dependent regulation of nuclear NAD(+) production, establishes an important pathway for transcription regulation by NAD(+)...
  17. pmc Diastereocontrolled electrophilic fluorinations of 2-deoxyribonolactone: syntheses of all corresponding 2-deoxy-2-fluorolactones and 2'-deoxy-2'-fluoro-NAD+s
    Yana Cen
    Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA
    J Org Chem 74:5779-89. 2009
    ..The fluorinated NAD(+)s are anticipated to be useful for studying a variety of cellular metabolic and signaling processes...