Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators. Hubbard, B. P., Gomes, A. P., Dai, H., Li, J., Case, A. W., Considine, T., Riera, T. V., Lee, J. E., E, S. Y., Lamming, D. W., Pentelute, B. L., 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, P. Y., Howitz, K. T., Rolo, A. P., Hamuro, Y., Moss, J., Perni, R. B., Ellis, J. L., Vlasuk, G. P., & Sinclair, D. A. Science, 339(6124):1216–1219, March, 2013. Publisher: American Association for the Advancement of Science Section: Report
Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators [link]Paper  doi  abstract   bibtex   
It's a SIRT Intense attention has focused on the SIRT1 deacetylase as a possible target for anti-aging drugs. But unexpected complications in assays of SIRT1 activity have made it unclear whether compounds thought to be sirtuin-activating compounds (STACs) are really direct regulators of the enzyme. Further exploration of these effects by Hubbard et al. (p. 1216; see the Perspective by Yuan and Marmorstein) revealed that interaction of SIRT1 with certain substrates allows activation of SIRT1 by STACs and identified critical amino acids in SIRT1 required for these effects. Mouse myoblasts reconstituted with SIRT1 mutated at this amino acid lost their responsiveness to STACs. 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, Glu230, 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. An interaction of the deacetylase SIRT1 with its substrate offers a possible explanation for some effects on aging. [Also see Perspective by Yuan and Marmorstein] An interaction of the deacetylase SIRT1 with its substrate offers a possible explanation for some effects on aging. [Also see Perspective by Yuan and Marmorstein]
@article{hubbard_evidence_2013,
	title = {Evidence for a {Common} {Mechanism} of {SIRT1} {Regulation} by {Allosteric} {Activators}},
	volume = {339},
	copyright = {Copyright © 2013, American Association for the Advancement of Science},
	issn = {0036-8075, 1095-9203},
	url = {https://science.sciencemag.org/content/339/6124/1216},
	doi = {10.1126/science.1231097},
	abstract = {It's a SIRT
Intense attention has focused on the SIRT1 deacetylase as a possible target for anti-aging drugs. But unexpected complications in assays of SIRT1 activity have made it unclear whether compounds thought to be sirtuin-activating compounds (STACs) are really direct regulators of the enzyme. Further exploration of these effects by Hubbard et al. (p. 1216; see the Perspective by Yuan and Marmorstein) revealed that interaction of SIRT1 with certain substrates allows activation of SIRT1 by STACs and identified critical amino acids in SIRT1 required for these effects. Mouse myoblasts reconstituted with SIRT1 mutated at this amino acid lost their responsiveness to STACs.
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, Glu230, 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.
An interaction of the deacetylase SIRT1 with its substrate offers a possible explanation for some effects on aging. [Also see Perspective by Yuan and Marmorstein]
An interaction of the deacetylase SIRT1 with its substrate offers a possible explanation for some effects on aging. [Also see Perspective by Yuan and Marmorstein]},
	language = {en},
	number = {6124},
	urldate = {2020-05-13},
	journal = {Science},
	author = {Hubbard, Basil P. and Gomes, Ana P. and Dai, Han and Li, Jun and Case, April W. and Considine, Thomas and Riera, Thomas V. and Lee, Jessica E. and E, Sook Yen and Lamming, Dudley W. and Pentelute, Bradley L. and Schuman, Eli R. and Stevens, Linda A. and Ling, Alvin J. Y. and Armour, Sean M. and Michan, Shaday and Zhao, Huizhen and Jiang, Yong and Sweitzer, Sharon M. and Blum, Charles A. and Disch, Jeremy S. and Ng, Pui Yee and Howitz, Konrad T. and Rolo, Anabela P. and Hamuro, Yoshitomo and Moss, Joel and Perni, Robert B. and Ellis, James L. and Vlasuk, George P. and Sinclair, David A.},
	month = mar,
	year = {2013},
	pmid = {23471411},
	note = {Publisher: American Association for the Advancement of Science
Section: Report},
	pages = {1216--1219},
}
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