期刊
SCIENCE
卷 339, 期 6124, 页码 1216-1219出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1231097
关键词
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资金
- Glenn Foundation for Medical Research
- Ellison Medical Foundation
- Juvenile Diabetes Research Foundation
- United Mitochondrial Disease Foundation
- NIH
- NIAID
- NSERC fellowship
- Portuguese Science and Technology Foundation
- Intramural Research Program
- NIH/NHLBI
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-1 alpha and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu(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.
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