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Synthesis of carba-NAD and the structures of its ternary complexes with SIRT3 and SIRT5.

Szczepankiewicz BG, Dai H, Koppetsch KJ, Qian D, Jiang F, Mao C, Perni RB
J Org Chem 77 7319-29 (2012)
Cited: 37 times
EuropePMC logo PMID: 22849721

Abstract

Carba-NAD is a synthetic compound identical to NAD except for one substitution, where an oxygen atom adjacent to the anomeric linkage bearing nicotinamide is replaced with a methylene group. Because it is inert in nicotinamide displacement reactions, carba-NAD is an unreactive substrate analogue for NAD-consuming enzymes. SIRT3 and SIRT5 are NAD-consuming enzymes that are potential therapeutic targets for the treatment of metabolic diseases and cancers. We report an improved carba-NAD synthesis, including a pyrophosphate coupling method that proceeds in approximately 60% yield. We also disclose the X-ray crystal structures of the ternary complexes of SIRT3 and SIRT5 bound to a peptide substrate and carba-NAD. These X-ray crystal structures provide critical snapshots of the mechanism by which human sirtuins function as protein deacylation catalysts.

Reviews - 4fvt mentioned but not cited (4)

  1. Structural biology of the writers, readers, and erasers in mono- and poly(ADP-ribose) mediated signaling. Karlberg T, Langelier MF, Pascal JM, Schüler H. Mol. Aspects Med. 34 1088-1108 (2013)
  2. Sirtuin activators and inhibitors: Promises, achievements, and challenges. Dai H, Sinclair DA, Ellis JL, Steegborn C. Pharmacol. Ther. 188 140-154 (2018)
  3. NAD Analogs in Aid of Chemical Biology and Medicinal Chemistry. Depaix A, Kowalska J. Molecules 24 (2019)
  4. Virtual Screening in the Identification of Sirtuins' Activity Modulators. Abbotto E, Scarano N, Piacente F, Millo E, Cichero E, Bruzzone S. Molecules 27 5641 (2022)

Articles - 4fvt mentioned but not cited (7)

  1. Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. Rumpf T, Schiedel M, Karaman B, Roessler C, North BJ, Lehotzky A, Oláh J, Ladwein KI, Schmidtkunz K, Gajer M, Pannek M, Steegborn C, Sinclair DA, Gerhardt S, Ovádi J, Schutkowski M, Sippl W, Einsle O, Jung M. Nat Commun 6 6263 (2015)
  2. Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies. Guan X, Lin P, Knoll E, Chakrabarti R. PLoS ONE 9 e107729 (2014)
  3. Comparative modeling and benchmarking data sets for human histone deacetylases and sirtuin families. Xia J, Tilahun EL, Kebede EH, Reid TE, Zhang L, Wang XS. J Chem Inf Model 55 374-388 (2015)
  4. Structural Basis for Activation of Human Sirtuin 6 by Fluvastatin. You W, Steegborn C. ACS Med Chem Lett 11 2285-2289 (2020)
  5. AlloReverse: multiscale understanding among hierarchical allosteric regulations. Zha J, Li Q, Liu X, Lin W, Wang T, Wei J, Zhang Z, Lu X, Wu J, Ni D, Song K, Zhang L, Lu X, Lu S, Zhang J. Nucleic Acids Res 51 W33-W38 (2023)
  6. Molecular Mechanism of Sirtuin 1 Inhibition by Human Immunodeficiency Virus 1 Tat Protein. Adolph RS, Beck E, Schweimer K, Di Fonzo A, Weyand M, Rösch P, Wöhrl BM, Steegborn C. Life (Basel) 13 949 (2023)
  7. SIRT2i_Predictor: A Machine Learning-Based Tool to Facilitate the Discovery of Novel SIRT2 Inhibitors. Djokovic N, Rahnasto-Rilla M, Lougiakis N, Lahtela-Kakkonen M, Nikolic K. Pharmaceuticals (Basel) 16 127 (2023)


Reviews citing this publication (9)

  1. Metabolic mechanisms of epigenetic regulation. Meier JL. ACS Chem. Biol. 8 2607-2621 (2013)
  2. Using mitochondrial sirtuins as drug targets: disease implications and available compounds. Gertz M, Steegborn C. Cell. Mol. Life Sci. 73 2871-2896 (2016)
  3. New assays and approaches for discovery and design of Sirtuin modulators. Schutkowski M, Fischer F, Roessler C, Steegborn C. Expert Opin Drug Discov 9 183-199 (2014)
  4. 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 38 147-200 (2018)
  5. Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors. Yang L, Ma X, He Y, Yuan C, Chen Q, Li G, Chen X. Sci China Life Sci 60 249-256 (2017)
  6. Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics. Ali I, Conrad RJ, Verdin E, Ott M. Chem. Rev. 118 1216-1252 (2018)
  7. Therapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5. Fiorentino F, Castiello C, Mai A, Rotili D. J Med Chem 65 9580-9606 (2022)
  8. Emerging Roles of SIRT5 in Metabolism, Cancer, and SARS-CoV-2 Infection. Fabbrizi E, Fiorentino F, Carafa V, Altucci L, Mai A, Rotili D. Cells 12 852 (2023)
  9. Recent advances in inhibitors of sirtuin1/2: an update and perspective. Zhou Z, Ma T, Zhu Q, Xu Y, Zha X. Future Med Chem 10 907-934 (2018)

Articles citing this publication (17)

  1. Structural and functional analysis of human SIRT1. Davenport AM, Huber FM, Hoelz A. J. Mol. Biol. 426 526-541 (2014)
  2. Crystallographic structure of a small molecule SIRT1 activator-enzyme complex. Dai H, Case AW, Riera TV, Considine T, Lee JE, Hamuro Y, Zhao H, Jiang Y, Sweitzer SM, Pietrak B, Schwartz B, Blum CA, Disch JS, Caldwell R, Szczepankiewicz B, Oalmann C, Yee Ng P, White BH, Casaubon R, Narayan R, Koppetsch K, Bourbonais F, Wu B, Wang J, Qian D, Jiang F, Mao C, Wang M, Hu E, Wu JC, Perni RB, Vlasuk GP, Ellis JL. Nat Commun 6 7645 (2015)
  3. Structures of human sirtuin 3 complexes with ADP-ribose and with carba-NAD+ and SRT1720: binding details and inhibition mechanism. Nguyen GT, Schaefer S, Gertz M, Weyand M, Steegborn C. Acta Crystallogr. D Biol. Crystallogr. 69 1423-1432 (2013)
  4. Identification of novel SIRT3 inhibitor scaffolds by virtual screening. Salo HS, Laitinen T, Poso A, Jarho E, Lahtela-Kakkonen M. Bioorg. Med. Chem. Lett. 23 2990-2995 (2013)
  5. NAD+ analog reveals PARP-1 substrate-blocking mechanism and allosteric communication from catalytic center to DNA-binding domains. Langelier MF, Zandarashvili L, Aguiar PM, Black BE, Pascal JM. Nat Commun 9 844 (2018)
  6. Sirtuin 3 interacts with Lon protease and regulates its acetylation status. Gibellini L, Pinti M, Beretti F, Pierri CL, Onofrio A, Riccio M, Carnevale G, De Biasi S, Nasi M, Torelli F, Boraldi F, De Pol A, Cossarizza A. Mitochondrion 18 76-81 (2014)
  7. Deacylation Mechanism by SIRT2 Revealed in the 1'-SH-2'-O-Myristoyl Intermediate Structure. Wang Y, Fung YME, Zhang W, He B, Chung MWH, Jin J, Hu J, Lin H, Hao Q. Cell Chem Biol 24 339-345 (2017)
  8. Drug repurposing for ligand-induced rearrangement of Sirt2 active site-based inhibitors via molecular modeling and quantum mechanics calculations. Bharadwaj S, Dubey A, Kamboj NK, Sahoo AK, Kang SG, Yadava U. Sci Rep 11 10169 (2021)
  9. Synthesis of Stable NAD+ Mimics as Inhibitors for the Legionella pneumophila Phosphoribosyl Ubiquitylating Enzyme SdeC. Madern JM, Kim RQ, Misra M, Dikic I, Zhang Y, Ovaa H, Codée JDC, Filippov DV, van der Heden van Noort GJ. Chembiochem 21 2903-2907 (2020)
  10. carba Nicotinamide Adenine Dinucleotide Phosphate: Robust Cofactor for Redox Biocatalysis. Zachos I, Döring M, Tafertshofer G, Simon RC, Sieber V. Angew Chem Int Ed Engl 60 14701-14706 (2021)
  11. 14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface. Karlberg T, Hornyak P, Pinto AF, Milanova S, Ebrahimi M, Lindberg M, Püllen N, Nordström A, Löverli E, Caraballo R, Wong EV, Näreoja K, Thorsell AG, Elofsson M, De La Cruz EM, Björkegren C, Schüler H. Nat Commun 9 3785 (2018)
  12. Biophysical characterization of hit compounds for mechanism-based enzyme activation. Guan X, Upadhyay A, Munshi S, Chakrabarti R. PLoS ONE 13 e0194175 (2018)
  13. Facile chemoenzymatic synthesis of a novel stable mimic of NAD. Dai Z, Zhang XN, Nasertorabi F, Cheng Q, Pei H, Louie SG, Stevens RC, Zhang Y. Chem Sci 9 8337-8342 (2018)
  14. Chemoenzymatic Preparation of 4'-Thioribose NAD. Zhang XN, Dai Z, Cheng Q, Zhang Y. Curr Protoc Nucleic Acid Chem 77 e83 (2019)
  15. Molecular Mechanism of Sirtuin 1 Modulation by the AROS Protein. Weiss S, Adolph RS, Schweimer K, DiFonzo A, Meleshin M, Schutkowski M, Steegborn C. Int J Mol Sci 23 12764 (2022)
  16. Synthesis of novel N-cyclopentenyl-lactams using the Aubé reaction. Shinde MV, Ople RS, Sangtani E, Gonnade R, Reddy DS. Beilstein J Org Chem 11 1060-1067 (2015)
  17. Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors. Scarano N, Abbotto E, Musumeci F, Salis A, Brullo C, Fossa P, Schenone S, Bruzzone S, Cichero E. Int J Mol Sci 24 9363 (2023)


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