A theoretical study on the mechanism of camphor hydroxylation by compound I of cytochrome p450

Takashi Kamachi, Kazunari Yoshizawa

研究成果: ジャーナルへの寄稿記事

181 引用 (Scopus)

抄録

Mechanistic and energetic aspects for the conversion of camphor to 5-exo-hydroxycamphor by the compound I iron-oxo species of cytochrome P450 are discussed from B3LYP DFT calculations. This reaction occurs in a two-step manner along the lines that the oxygen rebound mechanism suggests. The activation energy for the first transition state of the H atom abstraction at the C5 atom of camphor is computed to be more than 20 kcal/mol. This H atom abstraction is the rate-determining step in this hydroxylation reaction, leading to a reaction intermediate that involves a carbon radical species and the iron-hydroxo species. The second transition state of the rebound step that connects the reaction intermediate and the product alcohol complex lies a few kcal/mol below that for the H atom abstraction on the doublet and quartet potential energy surfaces. This energetic feature allows the virtually barrierless recombination in both spin states, being consistent with experimentally observed high stereoselectivity and brief lifetimes of the reaction intermediate. The overall energetic profile of the catalytic mechanism of camphor hydroxylation particularly with respect to why the high activation energy for the H atom abstraction is accessible under physiological conditions is also considered and calculated. According to a proton source model involving Thr252, Asp251, and two solvent water molecules (Biochemisty 1998, 37, 9211), the energetics for the conversion of the iron-peroxo species to compound I is studied. A significant energy over 50 kcal/mol is released in the course of this dioxygen activation process. The energy released in this chemical process is an important driving force in alkane hydroxylation by cytochrome P450. This energy is used for the access to the high activation energy for the H atom abstraction.

元の言語英語
ページ(範囲)4652-4661
ページ数10
ジャーナルJournal of the American Chemical Society
125
発行部数15
DOI
出版物ステータス出版済み - 4 16 2003

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Camphor
Hydroxylation
Cytochrome P-450 Enzyme System
Theoretical Models
Reaction intermediates
Atoms
Iron
Chemical Phenomena
Iron Compounds
Oxygen
Alkanes
Activation energy
Genetic Recombination
Protons
Carbon
Alcohols
Stereoselectivity
Potential energy surfaces
Water
Discrete Fourier transforms

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

これを引用

A theoretical study on the mechanism of camphor hydroxylation by compound I of cytochrome p450. / Kamachi, Takashi; Yoshizawa, Kazunari.

:: Journal of the American Chemical Society, 巻 125, 番号 15, 16.04.2003, p. 4652-4661.

研究成果: ジャーナルへの寄稿記事

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abstract = "Mechanistic and energetic aspects for the conversion of camphor to 5-exo-hydroxycamphor by the compound I iron-oxo species of cytochrome P450 are discussed from B3LYP DFT calculations. This reaction occurs in a two-step manner along the lines that the oxygen rebound mechanism suggests. The activation energy for the first transition state of the H atom abstraction at the C5 atom of camphor is computed to be more than 20 kcal/mol. This H atom abstraction is the rate-determining step in this hydroxylation reaction, leading to a reaction intermediate that involves a carbon radical species and the iron-hydroxo species. The second transition state of the rebound step that connects the reaction intermediate and the product alcohol complex lies a few kcal/mol below that for the H atom abstraction on the doublet and quartet potential energy surfaces. This energetic feature allows the virtually barrierless recombination in both spin states, being consistent with experimentally observed high stereoselectivity and brief lifetimes of the reaction intermediate. The overall energetic profile of the catalytic mechanism of camphor hydroxylation particularly with respect to why the high activation energy for the H atom abstraction is accessible under physiological conditions is also considered and calculated. According to a proton source model involving Thr252, Asp251, and two solvent water molecules (Biochemisty 1998, 37, 9211), the energetics for the conversion of the iron-peroxo species to compound I is studied. A significant energy over 50 kcal/mol is released in the course of this dioxygen activation process. The energy released in this chemical process is an important driving force in alkane hydroxylation by cytochrome P450. This energy is used for the access to the high activation energy for the H atom abstraction.",
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