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学科主题: 物理化学
题名: Reaction pathways and free energy profiles for cholinesterase-catalyzed hydrolysis of 6-monoacetylmorphine
作者: Qiao, Yan1, 2;  Han, Keli1;  Zhan, Chang-Guo2
通讯作者: 韩克利 ;  Chang-GuoZhan
刊名: ORGANIC & BIOMOLECULAR CHEMISTRY
发表日期: 2014
DOI: 10.1039/c3ob42464b
卷: 12, 期:14, 页:2214-2227
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Organic
研究领域[WOS]: Chemistry
英文摘要: As the most active metabolite of heroin, 6-monoacetylmorphine (6-MAM) can penetrate into the brain for the rapid onset of heroin effects. The primary enzymes responsible for the metabolism of 6-MAM to the less potent morphine in humans are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The detailed reaction pathways for AChE- and BChE-catalyzed hydrolysis of 6-MAM to morphine have been explored, for the first time, in the present study by performing first-principles quantum mechanical/molecular mechanical free energy calculations. It has been demonstrated that the two enzymatic reaction processes follow similar catalytic reaction mechanisms, and the whole catalytic reaction pathway for each enzyme consists of four reaction steps. According to the calculated results, the second reaction step associated with the transition state TS2(a)/TS2(b) should be rate-determining for the AChE/BChE-catalyzed hydrolysis, and the free energy barrier calculated for the AChE-catalyzed hydrolysis (18.3 kcal mol(-1)) is 2.5 kcal mol(-1) lower than that for the BChE-catalyzed hydrolysis (20.8 kcal mol(-1)). The free energy barriers calculated for the AChE- and BChE-catalyzed reactions are in good agreement with the experimentally derived activation free energies (17.5 and 20.7 kcal mol(-1) for the AChE- and BChE-catalyzed reactions, respectively). Further structural analysis reveals that the aromatic residues Phe295 and Phe297 in the acyl pocket of AChE (corresponding to Leu286 and Val288 in BChE) contribute to the lower energy of TS2(a) relative to TS2(b). The obtained structural and mechanistic insights could be valuable for use in future rational design of a novel therapeutic treatment of heroin abuse.
关键词[WOS]: FUNDAMENTAL REACTION PATHWAY ;  HIGH-ACTIVITY MUTANTS ;  HUMAN BUTYRYLCHOLINESTERASE ;  QM/MM SIMULATIONS ;  TRANSITION-STATES ;  DIACETYLMORPHINE HEROIN ;  MECHANICAL METHODS ;  ENZYME-REACTIONS ;  COCAINE ;  MORPHINE
语种: 英语
WOS记录号: WOS:000333037500009
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/143906
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, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA

Recommended Citation:
Qiao, Yan,Han, Keli,Zhan, Chang-Guo. Reaction pathways and free energy profiles for cholinesterase-catalyzed hydrolysis of 6-monoacetylmorphine[J]. ORGANIC & BIOMOLECULAR CHEMISTRY,2014,12(14):2214-2227.
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