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Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators

Author(s)
Hubbard, B. P.; Gomes, A. P.; Dai, H.; Li, J.; Case, A. W.; Considine, T.; Riera, T. V.; Lee, J. E.; Yen, E. Sook; Lamming, D. W.; Schuman, E. R.; Stevens, L. A.; Ling, A. J. Y.; Armour, S. M.; Michan, S.; Zhao, H.; Jiang, Y.; Sweitzer, S. M.; Blum, C. A.; Disch, J. S.; Ng, Pui Yee; Howitz, K. T.; Rolo, A. P.; Hamuro, Y.; Moss, Joel; Perni, R. B.; Ellis, J. L.; Vlasuk, G. P.; Sinclair, D. A.; Pentelute, Bradley L.; ... Show more Show less
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Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/
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Abstract
A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu[superscript 230], located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.
Date issued
2013-03
URI
http://hdl.handle.net/1721.1/82553
Department
Massachusetts Institute of Technology. Department of Chemistry
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Hubbard, B. P., A. P. Gomes, H. Dai, J. Li, A. W. Case, T. Considine, T. V. Riera, et al. “Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators.” Science 339, no. 6124 (March 7, 2013): 1216-1219.
Version: Author's final manuscript
ISSN
0036-8075
1095-9203

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