Sinclair David A, Guarente Leonard
Glenn Laboratories for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115; email:
Annu Rev Pharmacol Toxicol. 2014;54:363-80. doi: 10.1146/annurev-pharmtox-010611-134657. Epub 2013 Oct 16.
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.
哺乳动物的沉默调节蛋白（SIRT1 - 7）是依赖烟酰胺腺嘌呤二核苷酸（NAD⁺）的赖氨酸脱酰基酶，在细胞存活、炎症、能量代谢和衰老过程中发挥核心作用。该酶家族的成员被认为是治疗包括癌症、2型糖尿病、炎症性疾病和阿尔茨海默病在内的与年龄相关疾病的有前景的药物靶点。已从多种化学类别中鉴定出的SIRT1激活化合物（STACs）在动物疾病模型中具有有益健康的作用。最近的数据表明，天然和合成STACs的变构激活存在共同机制，即STACs与SIRT1中保守的N端结构域结合。与白藜芦醇等多酚相比，合成STACs表现出更强的效力、溶解性和靶点选择性。尽管在SIRT1变构激活方面已取得相当大的进展，但关键问题仍然存在，包括分子接触如何促进SIRT1激活、其他沉默调节蛋白家族成员是否适合激活，以及STACs最终是否在人类中被证明是安全有效的。
