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题名: Fundamental Reaction Pathways for Cytochrome P450-Catalyzed 5 '-Hydroxylation and N-Demethylation of Nicotine
作者: Li, Dongmei1, 2;  Wang, Yong1;  Han, Keli1;  Zhan, Chang-Guo2
刊名: JOURNAL OF PHYSICAL CHEMISTRY B
发表日期: 2010-07-15
DOI: 10.1021/jp102225e
卷: 114, 期:27, 页:9023-9030
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Physical
研究领域[WOS]: Chemistry
英文摘要: The reaction pathways for 5'-hydroxylation and N-demethylation of nicotine catalyzed by cytochrome P450 were investigated by performing a series of first-principle electronic structure calculations on a catalytic reaction model system. The computational results indicate that 5'-hydroxylation of nicotine occurs through a two-state stepwise process, that is, an initial hydrogen atom transfer from nicotine to Cpd 1 (i.e., the HAT step) followed by a recombination of the nicotine moiety with the iron-bound hydroxyl group (i.e., the rebound step) on both the high-spin (HS) quartet and low-spin (LS) doublet states. The HAT step is the rate-determining one. This finding represents the first case that exhibits genuine rebound transition state species on both the HS and the LS states for C(alpha)-H hydroxylation of amines. N-Demethylation of nicotine involves a N-methylhydroxylation to form N-(hydroxymethyl)nornicotine, followed by N-(hydroxymethyl)nornicotine decomposition to nornicotine and formaldehyde. The N-methylhydroxylation step is similar to 5'-hydroxylation, namely, a rate-determining HAT step followed by a rebound step. The decomposition process occurs on the deprotonated state of N-(hydroxymethyl)nornicotine assisted by a water molecule, and the energy barrier is significantly lower than that of the N-methylhydroxylation process. Comparison of the rate-determining free energy barriers for the two reaction pathways predicts a preponderance of 5'-hydroxylation over the N-demethylation by roughly a factor of 18: I, which is in excellent agreement with the factor of 19:1 derived from available experimental data.
关键词[WOS]: HUMAN LIVER-MICROSOMES ;  DENSITY-FUNCTIONAL THERMOCHEMISTRY ;  C-H HYDROXYLATION ;  SMOKING-CESSATION ;  COMPOUND-I ;  ALKANE HYDROXYLATION ;  ENZYMATIC OXIDATION ;  ALDEHYDE OXIDASE ;  REBOUND STEP ;  METABOLISM
语种: 英语
WOS记录号: WOS:000279507800026
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/141873
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:
Li, Dongmei,Wang, Yong,Han, Keli,et al. Fundamental Reaction Pathways for Cytochrome P450-Catalyzed 5 '-Hydroxylation and N-Demethylation of Nicotine[J]. JOURNAL OF PHYSICAL CHEMISTRY B,2010,114(27):9023-9030.
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