Resveratrol, the natural compound in red wine, and other small molecules are allosteric activators of SIRT1, an enzyme with roles in many biological processes (including DNA repair, metabolism, programmed cell death, and inflammation) that affect human life span. Studies have shown that Sirtuin activators like resveratrol can extend the lifespan of yeast, worms, and flies.
From an editor's summary of work by Hubbard et al
in the latest issue of Science:
Intense attention has focused on the SIRT1 deacetylase as a possible target for anti-aging drugs. But unexpected complications in assays of SIRT1 activity have made it unclear whether compounds thought to be sirtuin-activating compounds (STACs) are really direct regulators of the enzyme. Further exploration of these effects by Hubbard et al. revealed that interaction of SIRT1 with certain substrates allows activation of SIRT1 by STACs and identified critical amino acids in SIRT1 required for these effects. Mouse myoblasts reconstituted with SIRT1 mutated at this amino acid lost their responsiveness to STACs.
The Hubbard et al
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, Glu230, 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.
Drug design based on knowledge of the drug’s three-dimensional structure and how its shape and charge cause it to interact with its biological target, ultimately eliciting a medical effect.ReplyDelete