Sauve Anthony A
Weill Medical College of Cornell University, New York, NY 10065, USA.
Curr Pharm Des. 2009;15(1):45-56. doi: 10.2174/138161209787185797.
The sirtuins are protein modifying enzymes widely distributed in all forms of life. The sirtuins are principally NAD(+)-dependent protein acetyl-lysine deacetylases that reverse acetyl-modifications of proteins. The sirtuins are implicated in a variety of adaptations to reduced nutritional intake, and increase lifespan in several model organisms, such as yeast, flies and worms. The human sirtuins (SIRT1-7) have been identified to regulate a variety of biological processes, such as glucose homeostasis, gluconeogenesis, mitochondrial biogenesis, insulin secretion, adipogenesis and adipolysis, apoptosis, senescence and metabolism. The potency of sirtuins in regulating mammalian biological processes invites consideration of them as potential drug targets. This review considers small molecule approaches to activate sirtuins in a biochemical and biological context. These approaches include allosteric activation, which has been demonstrated for the SIRT1 enzyme. Another approach discussed is enhancement of NAD+ levels in cells, since sirtuins appear to be responsive to increased cellular NAD+. Finally, a sirtuin-specific approach is considered that is called nicotinamide derepression. This approach is designed to antagonize physiologic nicotinamide inhibition of sirtuins as a means to upregulate sirtuin function. Biological data that provides evidence of effectiveness of these approaches in in vitro and in vivo contexts is presented along with a discussion of the theoretical considerations that underpin these strategies. Efficacies and shortcomings of the various approaches are also discussed.
沉默调节蛋白是广泛分布于所有生命形式中的蛋白质修饰酶。沉默调节蛋白主要是依赖烟酰胺腺嘌呤二核苷酸（NAD⁺）的蛋白质乙酰赖氨酸脱乙酰酶，可逆转蛋白质的乙酰化修饰。沉默调节蛋白与多种应对营养摄入减少的适应性反应有关，并能延长酵母、果蝇和线虫等几种模式生物的寿命。已确定人类沉默调节蛋白（SIRT1 - 7）可调节多种生物学过程，如葡萄糖稳态、糖异生、线粒体生物发生、胰岛素分泌、脂肪生成和脂肪分解、细胞凋亡、衰老及代谢。沉默调节蛋白在调节哺乳动物生物学过程中的作用使其有望成为潜在的药物靶点。本综述探讨了在生化和生物学背景下激活沉默调节蛋白的小分子方法。这些方法包括变构激活，SIRT1酶已证实存在变构激活现象。讨论的另一种方法是提高细胞内NAD⁺水平，因为沉默调节蛋白似乎对细胞内NAD⁺水平升高有反应。最后，考虑了一种针对沉默调节蛋白的方法，即烟酰胺去抑制。该方法旨在拮抗生理状态下烟酰胺对沉默调节蛋白的抑制作用，从而上调沉默调节蛋白的功能。本文展示了在体外和体内环境中证明这些方法有效性的生物学数据，并讨论了支撑这些策略的理论依据。还讨论了各种方法的功效和缺点。
