Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Science (Impact Factor: 31.48). 03/2013; 339(6124):1216-9. DOI: 10.1126/science.1231097
Source: PubMed

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(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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