Mechanistic enzymology of oxygen activation by the cytochromes P450

Thomas M. Makris, Roman Davydov, Ilia G. Denisov, Brian M. Hoffman, Stephen G. Sligar

Research output: Contribution to journalReview articlepeer-review


The P450 cytochromes represent a universal class of heme-monooxygenases. The detailed mechanistic understanding of their oxidative prowess is a critical theme in the studies of metabolism of a wide range of organic compounds including xenobiotics. Integral to the 02 bond cleavage mechanism by P450 is the enzyme's concerted use of protein and solvent-mediated proton transfer events to transform reduced dioxygen to a species capable of oxidative chemistry. To this end, a wide range of kinetic, structural, and mutagenesis data has been accrued. A critical role of conserved acid-alcohol residues in the P450 distal pocket, as well as stabilized waters, enables the enzyme to catalyze effective monooxygenation chemistry. In this review, we discuss the detailed mechanism of P450 dioxygen scission utilizing the CYP101 hydroxylation of camphor as a model system. The application of low-temperature radiolytic techniques has enabled a structural and spectroscopic analysis of the nature of critical intermediate states in the reaction.

Original languageEnglish (US)
Pages (from-to)691-708
Number of pages18
JournalDrug Metabolism Reviews
Issue number4
StatePublished - 2002


  • CYP101
  • ENDOR spectra
  • EPR spectra
  • Monooxygenase
  • P450
  • Peroxo-ferric intermediate
  • Radiolytic reduction
  • UV/Vis spectra
  • X-ray crystallography

ASJC Scopus subject areas

  • General Pharmacology, Toxicology and Pharmaceutics
  • Pharmacology (medical)


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