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Fundamental Reaction Pathways for Cytochrome P450-Catalyzed 5 '-Hydroxylation and N-Demethylation of Nicotine
Li, Dongmei1,2; Wang, Yong1; Han, Keli1; Zhan, Chang-Guo2
刊名JOURNAL OF PHYSICAL CHEMISTRY B
2010-07-15
DOI10.1021/jp102225e
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
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
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.
语种英语
WOS记录号WOS:000279507800026
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文献类型期刊论文
条目标识符http://cas-ir.dicp.ac.cn/handle/321008/141873
专题中国科学院大连化学物理研究所
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
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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.
APA Li, Dongmei,Wang, Yong,Han, Keli,&Zhan, Chang-Guo.(2010).Fundamental Reaction Pathways for Cytochrome P450-Catalyzed 5 '-Hydroxylation and N-Demethylation of Nicotine.JOURNAL OF PHYSICAL CHEMISTRY B,114(27),9023-9030.
MLA Li, Dongmei,et al."Fundamental Reaction Pathways for Cytochrome P450-Catalyzed 5 '-Hydroxylation and N-Demethylation of Nicotine".JOURNAL OF PHYSICAL CHEMISTRY B 114.27(2010):9023-9030.
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