1szd Citations

Structural basis for nicotinamide cleavage and ADP-ribose transfer by NAD(+)-dependent Sir2 histone/protein deacetylases.

Proc. Natl. Acad. Sci. U.S.A. 101 8563-8 (2004)
Related entries: 1q1a, 1szc, 1q14, 1q17

Cited: 83 times
EuropePMC logo PMID: 15150415

Abstract

Sir2 enzymes are broadly conserved from bacteria to humans and have been implicated to play roles in gene silencing, DNA repair, genome stability, longevity, metabolism, and cell physiology. These enzymes bind NAD(+) and acetyllysine within protein targets and generate lysine, 2'-O-acetyl-ADP-ribose, and nicotinamide products. To provide structural insights into the chemistry catalyzed by Sir2 proteins we report the high-resolution ternary structure of yeast Hst2 (homologue of Sir two 2) with an acetyllysine histone H4 peptide and a nonhydrolyzable NAD(+) analogue, carba-NAD(+), as well as an analogous ternary complex with a reaction intermediate analog formed immediately after nicotinamide hydrolysis, ADP-ribose. The ternary complex with carba-NAD(+) reveals that the nicotinamide group makes stabilizing interactions within a binding pocket harboring conserved Sir2 residues. Moreover, an asparagine residue, N116, strictly conserved within Sir2 proteins and shown to be essential for nicotinamide exchange, is in position to stabilize the oxocarbenium intermediate that has been proposed to proceed the hydrolysis of nicotinamide. A comparison of this structure with the ADP-ribose ternary complex and a previously reported ternary complex with the 2'-O-acetyl-ADP-ribose reaction product reveals that the ribose ring of the cofactor and the highly conserved beta1-alpha2 loop of the protein undergo significant structural rearrangements to facilitate the ordered NAD(+) reactions of nicotinamide cleavage and ADP-ribose transfer to acetate. Together, these studies provide insights into the chemistry of NAD(+) cleavage and acetylation by Sir2 proteins and have implications for the design of Sir2-specific regulatory molecules.

Articles - 1szd mentioned but not cited (1)

  1. Hormonal control of androgen receptor function through SIRT1. Fu M, Liu M, Sauve AA, Jiao X, Zhang X, Wu X, Powell MJ, Yang T, Gu W, Avantaggiati ML, Pattabiraman N, Pestell TG, Wang F, Quong AA, Wang C, Pestell RG. Mol. Cell. Biol. 26 8122-8135 (2006)


Reviews citing this publication (37)

  1. The Current State of NAD(+) -Dependent Histone Deacetylases (Sirtuins) as Novel Therapeutic Targets. Schiedel M, Robaa D, Rumpf T, Sippl W, Jung M. Med Res Rev (2017)
  2. Chemical and structural biology of protein lysine deacetylases. Yoshida M, Kudo N, Kosono S, Ito A. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 93 297-321 (2017)
  3. Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells. Hwang ES, Song SB. Cell. Mol. Life Sci. 74 3347-3362 (2017)
  4. Potential Modulation of Sirtuins by Oxidative Stress. Santos L, Escande C, Denicola A. Oxid Med Cell Longev 2016 9831825 (2016)
  5. Epigenetic polypharmacology: from combination therapy to multitargeted drugs. de Lera AR, Ganesan A. Clin Epigenetics 8 105 (2016)
  6. The Substrate Specificity of Sirtuins. Bheda P, Jing H, Wolberger C, Lin H. Annu. Rev. Biochem. 85 405-429 (2016)
  7. Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases. Ramis MR, Esteban S, Miralles A, Tan DX, Reiter RJ. Mech. Ageing Dev. 146-148 28-41 (2015)
  8. Acylation of Biomolecules in Prokaryotes: a Widespread Strategy for the Control of Biological Function and Metabolic Stress. Hentchel KL, Escalante-Semerena JC. Microbiol. Mol. Biol. Rev. 79 321-346 (2015)
  9. Emerging role of silent information regulator 1 (SIRT1) in hepatocellular carcinoma: a potential therapeutic target. Wu Y, Meng X, Huang C, Li J. Tumour Biol. 36 4063-4074 (2015)
  10. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Hubbard BP, Sinclair DA. Trends Pharmacol. Sci. 35 146-154 (2014)
  11. Molecular Links between Caloric Restriction and Sir2/SIRT1 Activation. Wang Y. Diabetes Metab J 38 321-329 (2014)
  12. Role of CoA and acetyl-CoA in regulating cardiac fatty acid and glucose oxidation. Abo Alrob O, Lopaschuk GD. Biochem. Soc. Trans. 42 1043-1051 (2014)
  13. Modulation of epigenetic targets for anticancer therapy: clinicopathological relevance, structural data and drug discovery perspectives. Andreoli F, Barbosa AJ, Parenti MD, Del Rio A. Curr. Pharm. Des. 19 578-613 (2013)
  14. Sirtuins in neurodegenerative diseases: a biological-chemical perspective. Raghavan A, Shah ZA. Neurodegener Dis 9 1-10 (2012)
  15. Mitochondrial sirtuins and metabolic homeostasis. Pirinen E, Lo Sasso G, Auwerx J. Best Pract. Res. Clin. Endocrinol. Metab. 26 759-770 (2012)
  16. Structural basis for sirtuin activity and inhibition. Yuan H, Marmorstein R. J. Biol. Chem. 287 42428-42435 (2012)
  17. Catalysis and mechanistic insights into sirtuin activation. Dittenhafer-Reed KE, Feldman JL, Denu JM. Chembiochem 12 281-289 (2011)
  18. Sirtuin 1 (SIRT1): the misunderstood HDAC. Stünkel W, Campbell RM. J Biomol Screen 16 1153-1169 (2011)
  19. Protective effects and mechanisms of sirtuins in the nervous system. Zhang F, Wang S, Gan L, Vosler PS, Gao Y, Zigmond MJ, Chen J. Prog. Neurobiol. 95 373-395 (2011)
  20. The role of mammalian sirtuins in the regulation of metabolism, aging, and longevity. Satoh A, Stein L, Imai S. Handb Exp Pharmacol 206 125-162 (2011)
  21. Structural basis for sirtuin function: what we know and what we don't. Sanders BD, Jackson B, Marmorstein R. Biochim. Biophys. Acta 1804 1604-1616 (2010)
  22. Sirtuin chemical mechanisms. Sauve AA. Biochim. Biophys. Acta 1804 1591-1603 (2010)
  23. Chemical mechanisms of histone lysine and arginine modifications. Smith BC, Denu JM. Biochim. Biophys. Acta 1789 45-57 (2009)
  24. Sirtuin/Sir2 phylogeny, evolutionary considerations and structural conservation. Greiss S, Gartner A. Mol. Cells 28 407-415 (2009)
  25. Explorative study on isoform-selective histone deacetylase inhibitors. Suzuki T. Chem. Pharm. Bull. 57 897-906 (2009)
  26. Mechanisms and molecular probes of sirtuins. Smith BC, Hallows WC, Denu JM. Chem. Biol. 15 1002-1013 (2008)
  27. Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design. Hodawadekar SC, Marmorstein R. Oncogene 26 5528-5540 (2007)
  28. Nicotinamide adenine dinucleotide: beyond a redox coenzyme. Lin H. Org. Biomol. Chem. 5 2541-2554 (2007)
  29. The biochemistry of sirtuins. Sauve AA, Wolberger C, Schramm VL, Boeke JD. Annu. Rev. Biochem. 75 435-465 (2006)
  30. Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going? Hassa PO, Haenni SS, Elser M, Hottiger MO. Microbiol. Mol. Biol. Rev. 70 789-829 (2006)
  31. Nampt/PBEF/Visfatin: a regulator of mammalian health and longevity? Yang H, Lavu S, Sinclair DA. Exp. Gerontol. 41 718-726 (2006)
  32. The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension. Porcu M, Chiarugi A. Trends Pharmacol. Sci. 26 94-103 (2005)
  33. Epigenetics--an epicenter of gene regulation: histones and histone-modifying enzymes. Biel M, Wascholowski V, Giannis A. Angew. Chem. Int. Ed. Engl. 44 3186-3216 (2005)
  34. Transcriptional regulation of neuronal genes and its effect on neural functions: NAD-dependent histone deacetylase SIRT1 (Sir2alpha). Hisahara S, Chiba S, Matsumoto H, Horio Y. J. Pharmacol. Sci. 98 200-204 (2005)
  35. Vitamin B3 and sirtuin function. Denu JM. Trends Biochem. Sci. 30 479-483 (2005)
  36. Sirtuins (histone deacetylases III) in the cellular response to DNA damage--facts and hypotheses. Kruszewski M, Szumiel I. DNA Repair (Amst.) 4 1306-1313 (2005)
  37. The Sir 2 family of protein deacetylases. Denu JM. Curr Opin Chem Biol 9 431-440 (2005)

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  1. Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme. Avalos JL, Bever KM, Wolberger C. Mol. Cell 17 855-868 (2005)
  2. Structure of a human ASF1a-HIRA complex and insights into specificity of histone chaperone complex assembly. Tang Y, Poustovoitov MV, Zhao K, Garfinkel M, Canutescu A, Dunbrack R, Adams PD, Marmorstein R. Nat. Struct. Mol. Biol. 13 921-929 (2006)
  3. Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by suramin. Schuetz A, Min J, Antoshenko T, Wang CL, Allali-Hassani A, Dong A, Loppnau P, Vedadi M, Bochkarev A, Sternglanz R, Plotnikov AN. Structure 15 377-389 (2007)
  4. Structure and biochemical functions of SIRT6. Pan PW, Feldman JL, Devries MK, Dong A, Edwards AM, Denu JM. J. Biol. Chem. 286 14575-14587 (2011)
  5. Insights into the sirtuin mechanism from ternary complexes containing NAD+ and acetylated peptide. Hoff KG, Avalos JL, Sens K, Wolberger C. Structure 14 1231-1240 (2006)
  6. Crystal structures of human SIRT3 displaying substrate-induced conformational changes. Jin L, Wei W, Jiang Y, Peng H, Cai J, Mao C, Dai H, Choy W, Bemis JE, Jirousek MR, Milne JC, Westphal CH, Perni RB. J. Biol. Chem. 284 24394-24405 (2009)
  7. A molecular mechanism for direct sirtuin activation by resveratrol. Gertz M, Nguyen GT, Fischer F, Suenkel B, Schlicker C, Fränzel B, Tomaschewski J, Aladini F, Becker C, Wolters D, Steegborn C. PLoS ONE 7 e49761 (2012)
  8. Design and synthesis of compounds that extend yeast replicative lifespan. Yang H, Baur JA, Chen A, Miller C, Adams JK, Kisielewski A, Howitz KT, Zipkin RE, Sinclair DA. Aging Cell 6 35-43 (2007)
  9. Sir2 protein deacetylases: evidence for chemical intermediates and functions of a conserved histidine. Smith BC, Denu JM. Biochemistry 45 272-282 (2006)
  10. Structural basis for nicotinamide inhibition and base exchange in Sir2 enzymes. Sanders BD, Zhao K, Slama JT, Marmorstein R. Mol. Cell 25 463-472 (2007)
  11. Highly dissociative and concerted mechanism for the nicotinamide cleavage reaction in Sir2Tm enzyme suggested by ab initio QM/MM molecular dynamics simulations. Hu P, Wang S, Zhang Y. J. Am. Chem. Soc. 130 16721-16728 (2008)
  12. Bypassing the catalytic activity of SIR2 for SIR protein spreading in Saccharomyces cerevisiae. Yang B, Kirchmaier AL. Mol. Biol. Cell 17 5287-5297 (2006)
  13. SIRT3 substrate specificity determined by peptide arrays and machine learning. Smith BC, Settles B, Hallows WC, Craven MW, Denu JM. ACS Chem. Biol. 6 146-157 (2011)
  14. Human sirt-1: molecular modeling and structure-function relationships of an unordered protein. Autiero I, Costantini S, Colonna G. PLoS ONE 4 e7350 (2009)
  15. The bicyclic intermediate structure provides insights into the desuccinylation mechanism of human sirtuin 5 (SIRT5). Zhou Y, Zhang H, He B, Du J, Lin H, Cerione RA, Hao Q. J. Biol. Chem. 287 28307-28314 (2012)
  16. Primers on chromatin. Lall S. Nat. Struct. Mol. Biol. 14 1110-1115 (2007)
  17. Insights into the impact of histone acetylation and methylation on Sir protein recruitment, spreading, and silencing in Saccharomyces cerevisiae. Yang B, Britton J, Kirchmaier AL. J. Mol. Biol. 381 826-844 (2008)
  18. Structural and functional analysis of human SIRT1. Davenport AM, Huber FM, Hoelz A. J. Mol. Biol. 426 526-541 (2014)
  19. 2-Anilinobenzamides as SIRT inhibitors. Suzuki T, Imai K, Nakagawa H, Miyata N. ChemMedChem 1 1059-1062 (2006)
  20. Structural basis for allosteric stimulation of Sir2 activity by Sir4 binding. Hsu HC, Wang CL, Wang M, Yang N, Chen Z, Sternglanz R, Xu RM. Genes Dev. 27 64-73 (2013)
  21. Biochemical characterization of Plasmodium falciparum Sir2, a NAD+-dependent deacetylase. Chakrabarty SP, Saikumari YK, Bopanna MP, Balaram H. Mol. Biochem. Parasitol. 158 139-151 (2008)
  22. Comparative and pharmacophore model for deacetylase SIRT1. Huhtiniemi T, Wittekindt C, Laitinen T, Leppänen J, Salminen A, Poso A, Lahtela-Kakkonen M. J. Comput. Aided Mol. Des. 20 589-599 (2006)
  23. Swapping the gene-specific and regional silencing specificities of the Hst1 and Sir2 histone deacetylases. Mead J, McCord R, Youngster L, Sharma M, Gartenberg MR, Vershon AK. Mol. Cell. Biol. 27 2466-2475 (2007)
  24. N(epsilon)-Modified lysine containing inhibitors for SIRT1 and SIRT2. Huhtiniemi T, Suuronen T, Lahtela-Kakkonen M, Bruijn T, Jääskeläinen S, Poso A, Salminen A, Leppänen J, Jarho E. Bioorg. Med. Chem. 18 5616-5625 (2010)
  25. Selective overexpression of human SIRT1 in adipose tissue enhances energy homeostasis and prevents the deterioration of insulin sensitivity with ageing in mice. Xu C, Bai B, Fan P, Cai Y, Huang B, Law IK, Liu L, Xu A, Tung C, Li X, Siu FM, Che CM, Vanhoutte PM, Wang Y. Am J Transl Res 5 412-426 (2013)
  26. Identification of a Class of Protein ADP-Ribosylating Sirtuins in Microbial Pathogens. Rack JG, Morra R, Barkauskaite E, Kraehenbuehl R, Ariza A, Qu Y, Ortmayer M, Leidecker O, Cameron DR, Matic I, Peleg AY, Leys D, Traven A, Ahel I. Mol. Cell 59 309-320 (2015)
  27. Knock-down of PQBP1 impairs anxiety-related cognition in mouse. Ito H, Yoshimura N, Kurosawa M, Ishii S, Nukina N, Okazawa H. Hum. Mol. Genet. 18 4239-4254 (2009)
  28. Theoretical framework for the histone modification network: modifications in the unstructured histone tails form a robust scale-free network. Hayashi Y, Senda T, Sano N, Horikoshi M. Genes Cells 14 789-806 (2009)
  29. Structure-function analysis of the yeast NAD+-dependent tRNA 2'-phosphotransferase Tpt1. Sawaya R, Schwer B, Shuman S. RNA 11 107-113 (2005)
  30. Mimetics of hormetic agents: stress-resistance triggers. Sonneborn JS. Dose Response 8 97-121 (2010)
  31. Damped-dynamics flexible fitting. Kovacs JA, Yeager M, Abagyan R. Biophys. J. 95 3192-3207 (2008)
  32. Sirtuin Deacetylation Mechanism and Catalytic Role of the Dynamic Cofactor Binding Loop. Shi Y, Zhou Y, Wang S, Zhang Y. J Phys Chem Lett 4 491-495 (2013)
  33. Interactomic and pharmacological insights on human sirt-1. Sharma A, Gautam V, Costantini S, Paladino A, Colonna G. Front Pharmacol 3 40 (2012)
  34. NADH oxidase activity of Bacillus subtilis nitroreductase NfrA1: insight into its biological role. Cortial S, Chaignon P, Iorga BI, Aymerich S, Truan G, Gueguen-Chaignon V, Meyer P, Moréra S, Ouazzani J. FEBS Lett. 584 3916-3922 (2010)
  35. News Sirtuins caught in the act. Smith BC, Denu JM. Structure 14 1207-1208 (2006)
  36. SIRT1 Protects Human Lens Epithelial Cells Against Oxidative Stress by Inhibiting p53-Dependent Apoptosis. Zheng T, Lu Y. Curr. Eye Res. 41 1068-1075 (2016)
  37. Calorie Restriction Prevents Metabolic Aging Caused by Abnormal SIRT1 Function in Adipose Tissues. Xu C, Cai Y, Fan P, Bai B, Chen J, Deng HB, Che CM, Xu A, Vanhoutte PM, Wang Y. Diabetes 64 1576-1590 (2015)
  38. New synthetic approach to paullones and characterization of their SIRT1 inhibitory activity. Soto S, Vaz E, Dell'Aversana C, Álvarez R, Altucci L, de Lera ÁR. Org. Biomol. Chem. 10 2101-2112 (2012)
  39. beta-1,2,3-Triazolyl-nucleosides as nicotinamide riboside mimics. Amigues EJ, Armstrong E, Dvorakova M, Migaud ME, Huang M. Nucleosides Nucleotides Nucleic Acids 28 238-259 (2009)
  40. Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins. Kang H, Oka S, Lee DY, Park J, Aponte AM, Jung YS, Bitterman J, Zhai P, He Y, Kooshapur H, Ghirlando R, Tjandra N, Lee SB, Kim MK, Sadoshima J, Chung JH. Nat Commun 8 15560 (2017)
  41. Physical nature of intermolecular interactions inside Sir2 homolog active site: molecular dynamics and ab initio study. Czeleń P, Czyżnikowska Ż. J Mol Model 22 120 (2016)
  42. A Genome-Wide Screen with Nicotinamide to Identify Sirtuin-Dependent Pathways in Saccharomyces cerevisiae. Choy JS, Qadri B, Henry L, Shroff K, Bifarin O, Basrai MA. G3 (Bethesda) 6 485-494 (2015)
  43. Insight into the Mechanism of Intramolecular Inhibition of the Catalytic Activity of Sirtuin 2 (SIRT2). Li J, Flick F, Verheugd P, Carloni P, Lüscher B, Rossetti G. PLoS ONE 10 e0139095 (2015)
  44. Entamoeba histolytica sirtuin EhSir2a deacetylates tubulin and regulates the number of microtubular assemblies during the cell cycle. Dam S, Lohia A. Cell. Microbiol. 12 1002-1014 (2010)
  45. Histone-deacetylase inhibitors may accelerate the aging process in stem cell-dependent mammals: stem cells, Ku70, and Drosophila at the crossroads. Tapia PC. Med. Hypotheses 66 332-336 (2006)


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