Theoretical Study of N-Demethylation of Substituted N,N-Dimethylanilines by Cytochrome P450: The Mechanistic Significance of Kinetic Isotope Effect Profiles

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• 作者：Yong Wang ; Devesh Kumar ; Chuanlu Yang ; Keli Han ; Sason Shaik
• 刊名：Journal of Physical Chemistry B
• 出版年：2007
• 出版时间：July 5, 2007
• 年：2007
• 卷：111
• 期：26
• 页码：7700 - 7710
• 全文大小：991K
• 年卷期：v.111,no.26(July 5, 2007)
• ISSN：1520-5207

文摘

The mechanism of N-demethylation of N,N-dimethylanilines (DMAs) by cytochrome P450, a highly debatedtopic 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 activespecies of the enzyme, Compound I (Cpd I), with four para-(H, Cl, CN, NO₂) substituted DMAs. Thecalculations resolve mechanistic controversies, offer a consistent mechanistic view, and reveal the followingfeatures: (a) the reaction pathways involve C-H hydroxylation by Cpd I followed by a nonenzymaticcarbinolamine decomposition. (b) C-H hydroxylation is initiated by a hydrogen atom transfer (HAT) stepthat possesses a "polar" character. As such, the HAT energy barriers correlate with the energy level of theHOMO 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) Thecomputed kinetic isotope effect profiles (KIEPs) for these scenarios match the experimentally determinedKIEPs. 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 laterposition along the H-transfer coordinate and the corresponding KIEs increases. (e) The generated carbinolanilinecan readily dissociate from the heme and decomposes in a nonenzymatic environment, which involves waterassisted proton shift.