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题名: Theoretical study of N-demethylation of substituted N,N-dimethylanilines by cytochrome P450: The mechanistic significance of kinetic isotope effect profiles
作者: Wang, Yong;  Kumar, Devesh;  Yang, Chuanlu;  Han, Keli;  Shaik, Sason
刊名: JOURNAL OF PHYSICAL CHEMISTRY B
发表日期: 2007-07-05
DOI: 10.1021/jp072347v
卷: 111, 期:26, 页:7700-7710
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 mechanism of N-demethylation of N,N-dimethylanilines (DMAs) by cytochrome P450, a highly debated topic in mechanistic bioinorganic chemistry (Karki, S. B.; Dinnocenczo, J. P.; Jones, J. P.; Korzekwa, K. R. J. Am. Chem. Soc. 1995, 117, 3657), is studied here using DFT calculations of the reactions of the active species of the enzyme, Compound I (Cpd I), with four para-(H, Cl, CN, NO2) substituted DMAs. The calculations resolve mechanistic controversies, offer a consistent mechanistic view, and reveal the following features: (a) the reaction pathways involve C-H hydroxylation by Cpd I followed by a nonenzymatic carbinolamine decomposition. (b) C-H hydroxylation is initiated by a hydrogen atom transfer (HAT) step that possesses a "polar" character. As such, the HAT energy barriers correlate with the energy level of the HOMO of the DMAs. (c) The series exhibits a switch from spin-selective reactivity for DMA and p-Cl-DMA to two-state reactivity, with low- and high-spin states, for p-CN-DMA and p-NO2-DMA. (d) The computed kinetic isotope effect profiles (KIEPs) for these scenarios match the experimentally determined KIEPs. Theory further shows that the KIEs and TS structures vary in a manner predicted by the Melander-Westheimer postulate: as the substituent becomes more electron withdrawing, the TS is shifted to a later position along the H-transfer coordinate and the corresponding KIEs increases. (e) The generated carbinolaniline can readily dissociate from the heme and decomposes in a nonenzymatic environment, which involves water assisted proton shift.
关键词[WOS]: ELECTRON-TRANSFER MECHANISM ;  C-H HYDROXYLATION ;  REBOUND MECHANISM ;  HYDROGEN ABSTRACTION ;  TERTIARY-AMINES ;  HORSERADISH-PEROXIDASE ;  DEALKYLATION REACTIONS ;  MICROSOMAL OXIDATION ;  ALKANE HYDROXYLATION ;  2-STATE REACTIVITY
语种: 英语
WOS记录号: WOS:000247599500030
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/140518
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.Hebrew Univ Jerusalem, Inst Chem, IL-91904 Jerusalem, Israel
2.Chinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React Dynam, Dalian 116023, Peoples R China
3.Hebrew Univ Jerusalem, Lise Meitner Minerva Ctr Computat Quantum Chem, IL-91904 Jerusalem, Israel
4.Yantai Normal Univ, Dept Phys, Yantai 264025, Peoples R China

Recommended Citation:
Wang, Yong,Kumar, Devesh,Yang, Chuanlu,et al. Theoretical study of N-demethylation of substituted N,N-dimethylanilines by cytochrome P450: The mechanistic significance of kinetic isotope effect profiles[J]. JOURNAL OF PHYSICAL CHEMISTRY B,2007,111(26):7700-7710.
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