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A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate

文献类型：期刊论文

作者Yu, Nian-Da2,3; Wang, Bing3; Li, Xin-Zhu1; Han, Hao-Zhen3; Liu, Dongxiang2,3
刊名MOLECULES
出版日期2022-05-01
卷号27期号:9页码:18
关键词SIRT1 activator covalent bond 2 '-O-acetyl-ADP-ribose deacetylase
DOI10.3390/molecules27092714
通讯作者Liu, Dongxiang(liudongxiang@simm.ac.cn)
英文摘要SIRT1, an NAD(+)-dependent deacetylase, catalyzes the deacetylation of proteins coupled with the breakdown of NAD(+) into nicotinamide and 2'-O-acetyl-ADP-ribose (OAADPr). Selective SIRT1 activators have potential clinical applications in atherosclerosis, acute renal injury, and Alzheimer's disease. Here, we found that the activity of the potent SIRT1 activator CWR is independent of the acetylated substrate. It adopts a novel mechanism to promote SIRT1 activity by covalently bonding to the anomeric C1' carbon of the ribose ring in OAADPr. In addition, CWR is highly selective for SIRT1, with no effect on SIRT2, SIRT3, SIRT5, or SIRT6. The longer distance between the anomeric C1' carbon of the ribose ring in OAADPr and Arg274 of SIRT1 (a conserved residue among sirtuins) than that between the anomeric C1' carbon in OAADPr and the Arg of SIRT2, SIRT3, SIRT5, and SIRT6, should be responsible for the high selectivity of CWR for SIRT1. This was confirmed by site-directed mutagenesis of SIRT3. Consistent with the in vitro assays, the activator also reduced the acetylation levels of p53 in a concentration-dependent manner via SIRT1 in cells. Our study provides a new perspective for designing SIRT1 activators that does not rely on the chemical moiety immediately C-terminal to the acetyl-lysine of the substrate.
WOS关键词D-AMINO-ACID ; SMALL-MOLECULE ACTIVATORS ; STRUCTURAL BASIS ; ADP-RIBOSE ; RESVERATROL ; DISCOVERY ; SRT1720 ; DEACETYLATION ; DEGRADATION ; INHIBITION
资助项目National Natural Science Foundation of China[81973239] ; National Natural Science Foundation of China[21672233]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:000795378100001
出版者MDPI
源URL[http://119.78.100.183/handle/2S10ELR8/301104]  
专题中国科学院上海药物研究所
通讯作者Liu, Dongxiang
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Univ Chinese Acad Sci, Coll Pharm, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Chem Biol, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yu, Nian-Da,Wang, Bing,Li, Xin-Zhu,et al. A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate[J]. MOLECULES,2022,27(9):18.
APA Yu, Nian-Da,Wang, Bing,Li, Xin-Zhu,Han, Hao-Zhen,&Liu, Dongxiang.(2022).A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate.MOLECULES,27(9),18.
MLA Yu, Nian-Da,et al."A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate".MOLECULES 27.9(2022):18.

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来源：上海药物研究所

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