Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators
By Basil P. Hubbard, A. P. Gomes, H. Dai, Jun Li, April W. Case, Thomas Considine, T. Riera, Jessica E. Lee, Sook Yen E, Dudley Lamming and 20 more. Science, 2013
612 citations recorded by the source corpus.
It's a SIRT 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. (p. 1216; see the Perspective by Yuan and Marmorstein) 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. An interaction of the deacetylase SIRT1 with its substrate offers a possible explanation for some effects on aging. [Also see Perspective by Yuan and Marmorstein] 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.
Subfields: Geriatrics and Gerontology
View Paper: https://www.semanticscholar.org/paper/6040754d26d7e8dc3bda99ecb1e4bbf7cd5521d4
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Geriatrics and Gerontology
Citations in the corpus
- Sirt1 and the Mitochondria (2016, background): “The mode of action of sirtuin-activating compounds (STACs), possibly via an allosteric mechanism, has been better clarified (Hubbard et al., 2013).”
- Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “showed that a single amino acid, Glu(230) located in a structured N-terminal domain of SIRT1, is critical for activation of SIRT1 induced by STACs through a common allosteric mechanism (Hubbard et al., 2013).”
- SIRT1 and other sirtuins in Metabolism (2013, background): “STACs target an allosteric site in SIRT1, which is separate from the catalytic domain, and thus activate the deacetylation of substrates containing lysines with nearby hydrophobic residues [48].”