Resveratrol is Not a Direct Activator of SIRT1 Enzyme Activity
Resveratrol is Not a Direct Activator of SIRT1 Enzyme Activity
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DOI：
10.1111/j.1747-0285.2009.00901.x
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发表时间：
2009-12-01
影响因子：
3
通讯作者：
Wang, Minghan
中科院分区：
文献类型：
--
作者：
Beher, Dirk;Wu, John;Wang, Minghan
白藜芦醇是一种植物多酚，能够产生有益的代谢效应，这些效应被认为在很大程度上是由NAD⁺依赖的蛋白去乙酰化酶SIRT1的激活所介导的。尽管使用一种肽底物（Fluor de Lys - SIRT1肽底物）声称白藜芦醇是一种真正的SIRT1激活剂，但最近的报道表明这一发现可能是一种实验假象，需要加以澄清。在此，我们表明：（i）Fluor de Lys - SIRT1肽是一种人工的SIRT1底物，因为在没有共价连接的荧光团时，该肽本身不是该酶的底物；（ii）在存在源自p53的肽底物或从细胞中分离的乙酰化PGC - 1α的情况下，白藜芦醇在体外不能激活SIRT1；（iii）尽管SIRT1在体外和基于细胞的实验中都能使PGC - 1α去乙酰化，但在这些条件下白藜芦醇没有激活SIRT1。基于这些观察结果，我们得出结论：白藜芦醇在各种模型中的药理作用不太可能是通过直接增强SIRT1酶的催化活性来介导的。因此，我们的数据对将白藜芦醇作为直接激活SIRT1的药理学工具的整体效用提出了质疑。
Resveratrol is a plant polyphenol capable of exerting beneficial metabolic effects which are thought to be mediated in large by the activation of the NAD+-dependent protein deacetylase SIRT1. Although resveratrol has been claimed to be a bona fide SIRT1 activator using a peptide substrate (Fluor de Lys-SIRT1 peptide substrate), recent reports indicate that this finding might be an experimental artifact and need to be clarified. Here, we show that: (i) the Fluor de Lys-SIRT1 peptide is an artificial SIRT1 substrate because in the absence of the covalently linked fluorophore the peptide itself is not a substrate of the enzyme, (ii) resveratrol does not activate SIRT1 in vitro in the presence of either a p53-derived peptide substrate or acetylated PGC-1 alpha isolated from cells, and (iii) although SIRT1 deacetylates PGC-1 alpha in both in vitro and cell-based assays, resveratrol did not activate SIRT1 under these conditions. Based on these observations, we conclude that the pharmacological effects of resveratrol in various models are unlikely to be mediated by a direct enhancement of the catalytic activity of the SIRT1 enzyme. In consequence, our data challenge the overall utility of resveratrol as a pharmacological tool to directly activate SIRT1.