1. Evidence for a common mechanism of SIRT1 regulation by allosteric activators.
- Author
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Hubbard BP, Gomes AP, Dai H, Li J, Case AW, Considine T, Riera TV, Lee JE, E SY, Lamming DW, Pentelute BL, Schuman ER, Stevens LA, Ling AJ, Armour SM, Michan S, Zhao H, Jiang Y, Sweitzer SM, Blum CA, Disch JS, Ng PY, Howitz KT, Rolo AP, Hamuro Y, Moss J, Perni RB, Ellis JL, Vlasuk GP, and Sinclair DA
- Subjects
- Allosteric Regulation, Amino Acid Motifs, Amino Acid Sequence, Amino Acid Substitution, Animals, Cells, Cultured, Enzyme Activation, Forkhead Box Protein O3, Forkhead Transcription Factors chemistry, Forkhead Transcription Factors genetics, Glutamic Acid chemistry, Glutamic Acid genetics, Heterocyclic Compounds, 4 or More Rings chemistry, Heterocyclic Compounds, 4 or More Rings pharmacology, Humans, Hydrophobic and Hydrophilic Interactions, Mice, Molecular Sequence Data, Myoblasts drug effects, Myoblasts enzymology, Protein Structure, Tertiary, Resveratrol, Sirtuin 1 genetics, Stilbenes chemistry, Substrate Specificity, Sirtuin 1 chemistry, Sirtuin 1 metabolism, Stilbenes pharmacology
- 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.
- Published
- 2013
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