期刊
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 54
卷 54, 期 -, 页码 363-380出版社
ANNUAL REVIEWS
DOI: 10.1146/annurev-pharmtox-010611-134657
关键词
aging; sirtuin; NAD; allosteric activation; HDAC
资金
- NATIONAL INSTITUTE ON AGING [R01AG019719, R01AG028730, R37AG028730, R01AG015339] Funding Source: NIH RePORTER
- NIA NIH HHS [R01 AG015339, R01 AG019719, R01 AG028730, R37 AG028730, R56 AG015339] Funding Source: Medline
The mammalian sirtuins (SIRT1-7) are NAD(+)-dependent lysine deacylases that play central roles in cell survival, inflammation, energy metabolism, and aging. Members of this family of enzymes are considered promising pharmaceutical targets for the treatment of age-related diseases including cancer, type 2 diabetes, inflammatory disorders, and Alzheimer's disease. SIRT1-activating compounds (STACs), which have been identified from a variety of chemical classes, provide health benefits in animal disease models. Recent data point to a common mechanism of allosteric activation by natural and synthetic STACs that involves the binding of STACs to a conserved N-terminal domain in SIRT1. Compared with polyphenols such as resveratrol, the synthetic STACs show greater potency, solubility, and target selectivity. Although considerable progress has been made regarding SIRT1 allosteric activation, key questions remain, including how the molecular contacts facilitate SIRT1 activation, whether other sirtuin family members will be amenable to activation, and whether STACs will ultimately prove safe and efficacious in humans.
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