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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Allosteric Regulation
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Amino Acid Motifs
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Amino Acid Sequence
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Amino Acid Substitution
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Animals
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Cells, Cultured
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Enzyme Activation
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Forkhead Box Protein O3
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Forkhead Transcription Factors / chemistry
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Forkhead Transcription Factors / genetics
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Glutamic Acid / chemistry
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Glutamic Acid / genetics
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Heterocyclic Compounds, 4 or More Rings / chemistry
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Humans
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Hydrophobic and Hydrophilic Interactions
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Mice
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Molecular Sequence Data
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Myoblasts / drug effects
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Myoblasts / enzymology
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Protein Structure, Tertiary
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Resveratrol
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Sirtuin 1 / chemistry*
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Sirtuin 1 / genetics
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Sirtuin 1 / metabolism*
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Stilbenes / chemistry
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Stilbenes / pharmacology*
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Substrate Specificity
Substances
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FOXO3 protein, human
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Heterocyclic Compounds, 4 or More Rings
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SRT1460
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Stilbenes
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Glutamic Acid
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Sirtuin 1
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Resveratrol