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学科主题物理化学
Fundamental Reaction Pathway and Free Energy Profile for Butyrylcholinesterase-Catalyzed Hydrolysis of Heroin
Qiao, Yan1,2; Han, Keli1; Zhan, Chang-Guo2; Han KL(韩克利); CHANG-GUO ZHAN
刊名BIOCHEMISTRY
2013-09-17
DOI10.1021/bi400709v
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
资助者1,1 ; 1,1 ; 1,1 ; 1,1
类目[WOS]Biochemistry & Molecular Biology
研究领域[WOS]Biochemistry & Molecular Biology
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
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.
语种英语
资助者1,1 ; 1,1 ; 1,1 ; 1,1
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WOS记录号WOS:000330099600017
引用统计
被引频次:22[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://cas-ir.dicp.ac.cn/handle/321008/119469
专题中国科学院大连化学物理研究所
通讯作者Han KL(韩克利); CHANG-GUO ZHAN
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
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Qiao, Yan,Han, Keli,Zhan, Chang-Guo,et al. Fundamental Reaction Pathway and Free Energy Profile for Butyrylcholinesterase-Catalyzed Hydrolysis of Heroin[J]. BIOCHEMISTRY,2013,52(37):6467-6479.
APA Qiao, Yan,Han, Keli,Zhan, Chang-Guo,韩克利,&CHANG-GUO ZHAN.(2013).Fundamental Reaction Pathway and Free Energy Profile for Butyrylcholinesterase-Catalyzed Hydrolysis of Heroin.BIOCHEMISTRY,52(37),6467-6479.
MLA Qiao, Yan,et al."Fundamental Reaction Pathway and Free Energy Profile for Butyrylcholinesterase-Catalyzed Hydrolysis of Heroin".BIOCHEMISTRY 52.37(2013):6467-6479.
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