Evidence for a common mechanism of SIRT1 regulation by allosteric activators

Science. 2013 Mar 8;339(6124):1216-9. doi: 10.1126/science.1231097.

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

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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 / chemistry*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Stilbenes / chemistry
  • Stilbenes / pharmacology*
  • Substrate Specificity

Substances

  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Heterocyclic Compounds, 4 or More Rings
  • SRT1460
  • Stilbenes
  • Glutamic Acid
  • Sirtuin 1
  • Resveratrol