Discovery and Mechanism Study of SIRT1 Activators that Promote the Deacetylation of Fluorophore-Labeled Substrate

doi:10.1021/jm301032j

	Discovery and Mechanism Study of SIRT1 Activators that Promote the Deacetylation of Fluorophore-Labeled Substrate
	Wu, Jiahui 6; Zhang, Dengyou 5; Chen, Lei 6; Li, Jianneng 2; Wang, Jianling 4; Ning, Chengqing 3; Yu, Niefang 3; Zhao, Fei 5; Chen, Dongying4 ; Chen, Xiaoyan1
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2013-02-14
卷号	56 期号:3 页码:761-780
ISSN号	0022-2623
DOI	10.1021/jm301032j
文献子类	Article
英文摘要	SIRT1 is an NAD(+)-dependent deacetylase, whose activators have potential therapeutic applications in age-related diseases. Here we report a new class of SIRT1 activators. The activation is dependent on the fluorophore labeled to the substrate. To elucidate the activation mechanism, we solved the crystal structure of SIRT3/ac-RHKKac-AMC complex. The structure revealed that the fluorophore blocked the H-bond formation and created a cavity between the substrate and the Rossmann fold. We built the SIRT1/ac-RHKKac-AMC complex model based on the crystal structure. K-m and K-d determinations demonstrated that the fluorophore decreased the peptide binding affinity. The binding modes of SIRT1 activators indicated that a portion of the activators interacts with the fluorophore through pi-stacking, while the portion inserts into the cavity or interacts with the Rossmann fold, thus increasing the substrate affinity. Our study provides new insights into the mechanism of SIRT1 activation and may aid the design of novel SIRT1 activators.
资助项目	National Science Fund[21021063] ; National Science Fund[91229204] ; Science and Technology Commission of Shanghai Municipality[08JC1422100]
WOS关键词	SMALL-MOLECULE ACTIVATORS ; DEPENDENT PROTEIN DEACETYLASES ; LIFE-SPAN ; DROSOPHILA-MELANOGASTER ; CRYSTAL-STRUCTURE ; STRUCTURAL BASIS ; RESVERATROL ; SIRTUINS ; INHIBITORS ; COMPLEX
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000315182100013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277732]
专题	药物化学研究室药理学第三研究室
通讯作者	Liu, Dongxiang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet, Shanghai 201203, Peoples R China; 2.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China; 3.Cent S Univ, Sch Pharmaceut Sci, Inst Mol Design & Drug Discovery, Changsha 410078, Hunan, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, Shanghai 201203, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China; 6.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Pharmacol 3, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Wu, Jiahui,Zhang, Dengyou,Chen, Lei,et al. Discovery and Mechanism Study of SIRT1 Activators that Promote the Deacetylation of Fluorophore-Labeled Substrate[J]. JOURNAL OF MEDICINAL CHEMISTRY,2013,56(3):761-780.
APA	Wu, Jiahui.,Zhang, Dengyou.,Chen, Lei.,Li, Jianneng.,Wang, Jianling.,...&Liu, Dongxiang.(2013).Discovery and Mechanism Study of SIRT1 Activators that Promote the Deacetylation of Fluorophore-Labeled Substrate.JOURNAL OF MEDICINAL CHEMISTRY,56(3),761-780.
MLA	Wu, Jiahui,et al."Discovery and Mechanism Study of SIRT1 Activators that Promote the Deacetylation of Fluorophore-Labeled Substrate".JOURNAL OF MEDICINAL CHEMISTRY 56.3(2013):761-780.