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题名: Catalytic Mechanism of Cytochrome P450 for 5 '-Hydroxylation of Nicotine: Fundamental Reaction Pathways and Stereoselectivity
作者: Li, Dongmei1, 2;  Huang, Xiaoqin2;  Han, Keli1;  Zhan, Chang-Guo2
刊名: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
发表日期: 2011-05-18
DOI: 10.1021/ja111657j
卷: 133, 期:19, 页:7416-7427
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Multidisciplinary
研究领域[WOS]: Chemistry
英文摘要: A series of computational methods were used to study how cytochrome P450 2A6 (CYP2A6) interacts with (S)-(-)-nicotine, demonstrating that the dominant molecular species of (S)-(-)-nicotine in CYP2A6 active site exists in the free base state (with twb conformations, SRt and SRc), despite the fact that the protonated state is dominant for the free ligand in solution. The computational results reveal that the dominant pathway of nicotine metabolism in CYP2A6 is through nicotine free base oxidation. Further, first-principles quantum mechanical/molecular mechanical free energy (QM/MM-FE) calculations were carried out to uncover the detailed reaction pathways for the CYP2A6-catalyzed nicotine 5'-hydroxylation reaction. In the determined CYP2A6 (S)-(-)nicotine binding structures, the oxygen of Compound I (Cpd I) can abstract a hydrogen from either the trans-5'- or the cis-5' position of (S)-(-)-nicotine. CYP2A6-catalyzed (S)-(-)-nicotine 5'-hydroxylation consists of two reaction steps, that is, the hydrogen transfer from the 5'-position of (S)-(-)-nicotine to the oxygen of Cpd I (the H-transfer step), followed by the recombination of the (S)-(-)-nicotine moiety with the iron-bound hydroxyl group to generate the 5'-hydroxynicotine product (the O-rebound step). The H-transfer step is rate-determining. The 5'-hydroxylation proceeds mainly with the stereoselective loss of the trans-5'-hydrogen, that is, the 5'-hydrogen trans to the pyridine ring. The calculated overall stereoselectivity of similar to 97% favoring the trans-5'-hydroxylation is close to the observed stereoselectivity of 89-94%. This is the first time it has been demonstrated that a CYP substrate exists dominantly in one protonation state (cationic species) in solution, but uses its less-favorable protonation state (neutral free base) to perform the enzymatic reaction.
关键词[WOS]: AB-INITIO QM/MM ;  HUMAN LIVER-MICROSOMES ;  REACTION FIELD-THEORY ;  MOLECULAR-DYNAMICS ;  C-OXIDATION ;  ACTIVE-SITE ;  4-OXALOCROTONATE TAUTOMERASE ;  SMOKING-CESSATION ;  BINDING-AFFINITY ;  ALDEHYDE OXIDASE
语种: 英语
WOS记录号: WOS:000290782200038
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/142291
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:
Li, Dongmei,Huang, Xiaoqin,Han, Keli,et al. Catalytic Mechanism of Cytochrome P450 for 5 '-Hydroxylation of Nicotine: Fundamental Reaction Pathways and Stereoselectivity[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2011,133(19):7416-7427.
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