title: Theoretical study of N-demethylation of substituted N,N-dimethylanilines by cytochrome P450: the mechanistic significance of kinetic isotope effect profiles.
abstract: 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.
authors.affiliation: State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Devesh
authors.initials: D
authors.lastname: Kumar
authors.forename: Chuanlu
authors.initials: C
authors.lastname: Yang
authors.forename: Keli
authors.initials: K
authors.lastname: Han
authors.forename: Sason
authors.initials: S
authors.lastname: Shaik
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D003640:Dealkylation; D007553:Isotope Labeling; D007700:Kinetics
chemical_list: D000814:Aniline Compounds; C015157:N,N-dimethylaniline; D003577:Cytochrome P-450 Enzyme System