New features in the catalytic cycle of cytochrome P450 during the formation of Compound I from Compound 0

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

  • Devesh Kumar
  • Sam P. De Visser
  • Jingjing Zheng
  • Dongqi Wang
  • Walter Thiel
  • Sason Shaik

Detail(s)

Original languageEnglish
Pages (from-to)19946-19951
Journal / PublicationJournal of Physical Chemistry B
Volume109
Issue number42
Publication statusPublished - 27 Oct 2005
Externally publishedYes

Abstract

Density functional theory (DFT) is applied to the dark section of the catalytic cycle of the enzyme cytochrome P450, namely, the formation of the active species, Compound I (Cpd I), from the ferric-hydroperoxide species (Cpd 0) by a protonation-assisted mechanism. The chosen 96-atom model includes the key functionalities deduced from experiment: Asp251, Thr 252, Glu366, and the water channels that relay the protons. The DFT model calculations show that (a) Cpd I is not formed spontaneously from Cpd 0 by direct protonation, nor is the process very exothermic. The process is virtually thermoneutral and involves a significant barrier such that formation of Cpd I is not facile on this route, (b) Along the protonation pathway, there exists an intermediate, a protonated Cpd 0, which is a potent oxidant since it is a ferric complex of water oxide. Preliminary quantum mechanical/molecular mechanical calculations confirm that Cpd 0 and Cpd I are of similar energy for the chosen model and that protonated Cpd 0 may exist as an unstable intermediate. The paper also addresses the essential role of Thr252 as a hydrogen-bond acceptor (in accord with mutation studies of the OH group to OMe). © 2005 American Chemical Society.

Citation Format(s)

New features in the catalytic cycle of cytochrome P450 during the formation of Compound I from Compound 0. / Kumar, Devesh; Hirao, Hajime; De Visser, Sam P.; Zheng, Jingjing; Wang, Dongqi; Thiel, Walter; Shaik, Sason.

In: Journal of Physical Chemistry B, Vol. 109, No. 42, 27.10.2005, p. 19946-19951.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review