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学科主题: 物理化学
题名: Fundamental Reaction Pathway and Free Energy Profile for Butyrylcholinesterase-Catalyzed Hydrolysis of Heroin
作者: Qiao, Yan1, 2;  Han, Keli1;  Zhan, Chang-Guo2
通讯作者: 韩克利 ;  CHANG-GUO ZHAN
刊名: BIOCHEMISTRY
发表日期: 2013-09-17
DOI: 10.1021/bi400709v
卷: 52, 期:37, 页:6467-6479
收录类别: SCI
合作性质: 
文章类型: Article
部门归属: 11
项目归属: 1101
产权排名: 待补充
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Biochemistry & Molecular Biology
资助者: 1,1
研究领域[WOS]: Biochemistry & Molecular Biology
英文摘要: The pharmacological function of heroin requires an activation process that transforms heroin into 6-monoacetylmorphine (6-MAM), which is the most active form. The primary enzyme responsible for this activation process in human plasma is butyrylcholinesterase (BChE). The detailed reaction pathway of the activation process via BChE-catalyzed hydrolysis has been explored computationally, for the first time, in this study via molecular dynamics simulation and first-principles quantum mechanical/molecular mechanical free energy calculations. It has been demonstrated that the whole reaction process includes acylation and deacylation stages. The acylation consists of two reaction steps, i.e., the nucleophilic attack on the carbonyl carbon of the 3-acetyl group of heroin by the hydroxyl oxygen of the Ser198 side chain and the dissociation of 6-MAM. The deacylation also consists of two reaction steps, i.e., the nucleophilic attack on the carbonyl carbon of the acyl enzyme intermediate by a water molecule and the dissociation of the acetic acid from Ser198. The calculated free energy profile reveals that the second transition state (TS2) should be rate-determining. The structural analysis reveals that the oxyanion hole of BChE plays an important role in the stabilization of rate-determining TS2. The free energy barrier (15.9 +/- 0.2 or 16.1 +/- 0.2 kcal/mol) calculated for the rate-determining step is in good agreement with the experimentally derived activation free energy (similar to 16.2 kcal/mol), suggesting that the mechanistic insights obtained from this computational study are reliable. The obtained structural and mechanistic insights could be valuable for use in the future rational design of a novel therapeutic treatment of heroin abuse.
关键词[WOS]: AB-INITIO QM/MM ;  MOLECULAR-DYNAMICS SIMULATIONS ;  RATE-DETERMINING STEP ;  REACTION-MECHANISM ;  DIACETYLMORPHINE HEROIN ;  COCAINE ESTERASE ;  ENZYME-REACTIONS ;  FORCE-FIELD ;  HUMAN-SERUM ;  WILD-TYPE
语种: 英语
原文出处: 查看原文
WOS记录号: WOS:000330099600017
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/119469
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Chinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React Dynam, Dalian 116023, Peoples R China
2.Univ Kentucky, Dept Pharmaceut Sci, Coll Pharm, Lexington, KY 40536 USA

Recommended Citation:
Qiao, Yan,Han, Keli,Zhan, Chang-Guo. Fundamental Reaction Pathway and Free Energy Profile for Butyrylcholinesterase-Catalyzed Hydrolysis of Heroin[J]. BIOCHEMISTRY,2013,52(37):6467-6479.
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