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Discovery and mechanism study of SIRT1 activators that promote the deacetylation of fluorophore-labeled substrate.

Wu J, Zhang D, Chen L, Li J, Wang J, Ning C, Yu N, Zhao F, Chen D, Chen X, Chen K, Jiang H, Liu H, Liu D
J Med Chem 56 761-80 (2013)
Cited: 17 times
EuropePMC logo PMID: 23316803

Abstract

SIRT1 is an NAD(+)-dependent deacetylase, whose activators have potential therapeutic applications in age-related diseases. Here we report a new class of SIRT1 activators. The activation is dependent on the fluorophore labeled to the substrate. To elucidate the activation mechanism, we solved the crystal structure of SIRT3/ac-RHKK(ac)-AMC complex. The structure revealed that the fluorophore blocked the H-bond formation and created a cavity between the substrate and the Rossmann fold. We built the SIRT1/ac-RHKK(ac)-AMC complex model based on the crystal structure. K(m) and K(d) determinations demonstrated that the fluorophore decreased the peptide binding affinity. The binding modes of SIRT1 activators indicated that a portion of the activators interacts with the fluorophore through π-stacking, while the other portion inserts into the cavity or interacts with the Rossmann fold, thus increasing the substrate affinity. Our study provides new insights into the mechanism of SIRT1 activation and may aid the design of novel SIRT1 activators.

Articles - 4fz3 mentioned but not cited (1)

  1. 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)


Reviews citing this publication (4)

  1. Small-molecule allosteric activators of sirtuins. Sinclair DA, Guarente L. Annu Rev Pharmacol Toxicol 54 363-380 (2014)
  2. 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)
  3. Targeting mitochondrial alterations to prevent type 2 diabetes--evidence from studies of dietary redox-active compounds. Cheng Z, Schmelz EM, Liu D, Hulver MW. Mol Nutr Food Res 58 1739-1749 (2014)
  4. Human sirtuins: Structures and flexibility. Sacconnay L, Carrupt PA, Nurisso A. J Struct Biol 196 534-542 (2016)

Articles citing this publication (12)

  1. Cycloastragenol upregulates SIRT1 expression, attenuates apoptosis and suppresses neuroinflammation after brain ischemia. Li M, Li SC, Dou BK, Zou YX, Han HZ, Liu DX, Ke ZJ, Wang ZF. Acta Pharmacol Sin 41 1025-1032 (2020)
  2. Quantitative and systems pharmacology 4. Network-based analysis of drug pleiotropy on coronary artery disease. Fang J, Cai C, Chai Y, Zhou J, Huang Y, Gao L, Wang Q, Cheng F. Eur J Med Chem 161 192-204 (2019)
  3. Letter Crystal structures of SIRT3 reveal that the α2-α3 loop and α3-helix affect the interaction with long-chain acyl lysine. Gai W, Li H, Jiang H, Long Y, Liu D. FEBS Lett 590 3019-3028 (2016)
  4. Sticking and patching: tuning and anchoring cyclometallated ruthenium(II) complexes. Ertl CD, Ris DP, Meier SC, Constable EC, Housecroft CE, Neuburger M, Zampese JA. Dalton Trans 44 1557-1570 (2015)
  5. Molecular Imaging of Sirtuin1 Expression-Activity in Rat Brain Using Positron-Emission Tomography-Magnetic-Resonance Imaging with [18F]-2-Fluorobenzoylaminohexanoicanilide. Bonomi R, Popov V, Laws MT, Gelovani D, Majhi A, Shavrin A, Lu X, Muzik O, Turkman N, Liu R, Mangner T, Gelovani JG. J Med Chem 61 7116-7130 (2018)
  6. Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5. Han H, Li C, Li M, Yang L, Zhao S, Wang Z, Liu H, Liu D. Molecules 25 E2755 (2020)
  7. Rational design of novel sirtuin 1 activators via structure-activity insights from application of QSAR modeling. Pratiwi R, Prachayasittikul V, Prachayasittikul S, Nantasenamat C. EXCLI J 18 207-222 (2019)
  8. Search for a novel SIRT1 activator: structural modification of SRT1720 and biological evaluation. Matsuya Y, Kobayashi Y, Uchida S, Itoh Y, Sawada H, Suzuki T, Miyata N, Sugimoto K, Toyooka N. Bioorg Med Chem Lett 23 4907-4910 (2013)
  9. Discovery of 11β-hydroxysteroid dehydrogenase type 1 inhibitor. Hong SP, Nam KY, Shin YJ, Kim KW, Ahn SK. Bioorg Med Chem Lett 25 3501-3506 (2015)
  10. A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate. Yu ND, Wang B, Li XZ, Han HZ, Liu D. Molecules 27 2714 (2022)
  11. Letter Mechanism and design of allosteric activators of SIRT1. Liu F, Pang N, Xu RM, Yang N. Protein Cell 14 387-392 (2023)
  12. Synthesis of oxamide-hydrazone hybrid derivatives as potential anticancer agents. Dehbid M, Tahmasvand R, Tasharofi M, Shojaie F, Aghamaali M, Almasirad A, Salimi M. Res Pharm Sci 18 24-38 (2023)


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