Aromatic hydroxylation by cytochrome P450: model calculations of mechanism and substituent effects

Christine M Bathelt, Lars Ridder, Adrian J Mulholland, Jeremy N Harvey

Research output: Contribution to journalArticle (Academic Journal)peer-review

112 Citations (Scopus)

Abstract

The mechanism and selectivity of aromatic hydroxylation by cytochrome P450 enzymes is explored using new B3LYP density functional theory computations. The calculations, using a realistic porphyrin model system, show that rate-determining addition of compound I to an aromatic carbon atom proceeds via a transition state with partial radical and cationic character. Reactivity is shown to depend strongly on ring substituents, with both electron-withdrawing and -donating groups strongly decreasing the addition barrier in the para position, and it is shown that the calculated barrier heights can be reproduced by a new dual-parameter equation based on radical and cationic Hammett sigma parameters.

Original languageEnglish
Pages (from-to)15004-5
Number of pages2
JournalJournal of the American Chemical Society
Volume125
Issue number49
DOIs
Publication statusPublished - 10 Dec 2003

Keywords

  • Cytochrome P-450 Enzyme System
  • Hydrocarbons, Aromatic
  • Hydroxylation
  • Models, Molecular
  • Thermodynamics

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