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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
Source PublicationJOURNAL OF PHYSICAL CHEMISTRY B
2007-07-05
DOI10.1021/jp072347v
Volume111Issue:26Pages:7700-7710
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Physical Sciences
WOS SubjectChemistry, Physical
WOS Research AreaChemistry
WOS KeywordELECTRON-TRANSFER MECHANISM ; C-H HYDROXYLATION ; REBOUND MECHANISM ; HYDROGEN ABSTRACTION ; TERTIARY-AMINES ; HORSERADISH-PEROXIDASE ; DEALKYLATION REACTIONS ; MICROSOMAL OXIDATION ; ALKANE HYDROXYLATION ; 2-STATE REACTIVITY
AbstractThe 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.
Language英语
WOS IDWOS:000247599500030
Citation statistics
Cited Times:87[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/140518
Collection中国科学院大连化学物理研究所
Affiliation1.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
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.
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