Investigation of the Catalytic Mechanism of Sir2 Enzyme with QM/MM Approach: SN1 vs SN2?
文献类型：期刊论文
| 作者 | Liang, Zhongjie1; Shi, Ting1; Ouyang, Sisheng1; Li, Honglin2; Yu, Kunqian1 ; Zhu, Weiliang1,2; Luo, Cheng1,3; Jiang, Hualiang1,2
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| 刊名 | JOURNAL OF PHYSICAL CHEMISTRY B
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| 出版日期 | 2010-09-16 |
| 卷号 | 114期号:36页码:11927-11933 |
| ISSN号 | 1520-6106 |
| DOI | 10.1021/jp1054183 |
| 文献子类 | Article |
| 英文摘要 | Sir2, the histone deacetylase III family, has been subjected to a wide range of studies because of their crucial roles in DNA repair, longevity, transcriptional silencing, genome stability, apoptosis, and fat mobilization. The enzyme binds NAD(+) and acetyllysine as substrates and generates lysine, 2 '-O-acetyl-ADP-ribose, and nicotinamide as products. However, the mechanism of the first step in Sir2 deacetylation reaction from various studies is controversial. To characterize this catalytic mechanism of acetyllysine deacetylation by Sir2, we employed a combined computational approach to carry out molecular modeling, molecular dynamics (MD) simulations, quantum mechanics/molecular mechanics (QM/MM) calculations on catalysis by both yeast Hst2 (homologue of SIR two 2) and bacterial Sir2TM (Sir2 homologue from Thermatoga maritima). Our three-dimensional (3D) model of the complex is composed of Sir2 protein, NAD(+), and acetyllysine (ALY) substrate. A 15-ns MD simulation of the complex revealed that Gln115 and His135 play a determining role in deacetylation. These two residues can act as bases to facilitate the deprotonation of 2 '-OH from N-ribose. The result is in great agreement with previous mutagenesis analysis data. QM/MM calculations were further performed to study the mechanism of the first step in deacetylation in the two systems. The predicted potential energy barriers for yHst2 and Sir2TM are 12.0 and 15.7 kcal/mol, respectively. The characteristics of the potential energy surface indicated this reaction belongs to a SN2-like mechanism. These results provide insights into the Sir2 mechanism of nicotinamide inhibition and have important implications for the discovery of effectors against Sir2 enzymes. |
| WOS关键词 | HISTONE/PROTEIN DEACETYLASES ; CALORIE RESTRICTION ; STRUCTURAL BASIS ; MET KINASE ; LIFE-SPAN ; NICOTINAMIDE CLEAVAGE ; PROTEIN DEACETYLASES ; SIR2-LIKE PROTEINS ; CRYSTAL-STRUCTURE ; INHIBITORS |
| 资助项目 | National Natural Science Foundation of China[20720102040] ; National Natural Science Foundation of China[20803022] ; National Natural Science Foundation of China[20972174] ; Hi-Tech Research and Development Program of China[2006AA01A124] ; State Key Program of Basic Research of China[2009CB918502] ; State Key Program of Basic Research of China[2009CB940901] ; Shanghai Committee of Science and Technology[10410703900] ; National ST Major Project[2009ZX09501-001] ; Chinese Academy of Sciences[INFO-115-B01] ; State Key Laboratory[SIMM1004KF-15] ; Guangdong Science and Technology Department[2010A030100006] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000281404500027 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278774]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Luo, Cheng |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China; 2.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China; 3.Soochow Univ, Ctr Syst Biol, Suzhou 215006, Peoples R China |
| 推荐引用方式 GB/T 7714 | Liang, Zhongjie,Shi, Ting,Ouyang, Sisheng,et al. Investigation of the Catalytic Mechanism of Sir2 Enzyme with QM/MM Approach: SN1 vs SN2?[J]. JOURNAL OF PHYSICAL CHEMISTRY B,2010,114(36):11927-11933. |
| APA | Liang, Zhongjie.,Shi, Ting.,Ouyang, Sisheng.,Li, Honglin.,Yu, Kunqian.,...&Jiang, Hualiang.(2010).Investigation of the Catalytic Mechanism of Sir2 Enzyme with QM/MM Approach: SN1 vs SN2?.JOURNAL OF PHYSICAL CHEMISTRY B,114(36),11927-11933. |
| MLA | Liang, Zhongjie,et al."Investigation of the Catalytic Mechanism of Sir2 Enzyme with QM/MM Approach: SN1 vs SN2?".JOURNAL OF PHYSICAL CHEMISTRY B 114.36(2010):11927-11933. |
入库方式： OAI收割
来源：上海药物研究所
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