Theoretical study of N-demethylation of substituted N,N-dimethylanilines by cytochrome P450: The mechanistic significance of kinetic isotope effect profiles

	Theoretical study of N-demethylation of substituted N,N-dimethylanilines by cytochrome P450: The mechanistic significance of kinetic isotope effect profiles
	Wang, Yong ; Kumar, Devesh ; Yang, Chuanlu ; Han, Keli ; Shaik, Sason
刊名	journal of physical chemistry b
	2007-07-05
卷号	111 期号:26 页码:7700-7710
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.
WOS标题词	science & technology ; physical sciences
类目[WOS]	chemistry, physical
研究领域[WOS]	chemistry
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
收录类别	SCI
语种	英语
WOS记录号	WOS:000247599500030
公开日期	2015-11-17
内容类型	期刊论文
源URL	[http://159.226.238.44/handle/321008/140518]
专题	大连化学物理研究所_中国科学院大连化学物理研究所
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
推荐引用方式 GB/T 7714	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.
APA	Wang, Yong,Kumar, Devesh,Yang, Chuanlu,Han, Keli,&Shaik, Sason.(2007).Theoretical study of N-demethylation of substituted N,N-dimethylanilines by cytochrome P450: The mechanistic significance of kinetic isotope effect profiles.journal of physical chemistry b,111(26),7700-7710.
MLA	Wang, Yong,et al."Theoretical study of N-demethylation of substituted N,N-dimethylanilines by cytochrome P450: The mechanistic significance of kinetic isotope effect profiles".journal of physical chemistry b 111.26(2007):7700-7710.