作者
Basil P Hubbard, Ana P Gomes, Han Dai, Jun Li, April W Case, Thomas Considine, Thomas V Riera, Jessica E Lee, Sook Yen E, Dudley W Lamming, Bradley L Pentelute, Eli R Schuman, Linda A Stevens, Alvin JY Ling, Sean M Armour, Shaday Michan, Huizhen Zhao, Yong Jiang, Sharon M Sweitzer, Charles A Blum, Jeremy S Disch, Pui Yee Ng, Konrad T Howitz, Anabela P Rolo, Yoshitomo Hamuro, Joel Moss, Robert B Perni, James L Ellis, George P Vlasuk, David A Sinclair
发表日期
2013/3/8
期刊
Science
卷号
339
期号
6124
页码范围
1216-1219
出版商
American Association for the Advancement of Science
简介
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.
学术搜索中的文章
BP Hubbard, AP Gomes, H Dai, J Li, AW Case… - Science, 2013