Monooxygenation mechanism by cytochrome p-450

J Am Chem Soc. 2001 Jul 4;123(26):6410-6. doi: 10.1021/ja000908p.


The substrate oxygenation mechanism by an ultimate species in monooxygenation by cytochrome P-450 (compound I) was investigated by the density functional theory method. An initial model compound was constructed from a structure obtained by 300-ps molecular dynamics simulation of compound I-formed P-450cam under physiologic conditions, and it consisted of porphine for protoporphyrin IX, S(-)-CH(3) for the side chain of Cys357 of the fifth ligand of heme, a methane molecule for the substrate, a heme iron, and an oxygen atom of the sixth ligand of heme. The results of the calculation revealed that the substrate oxygenation mechanism had four elementary processes, i.e., (1) formation of [FeOH](3+) and a substrate radical by hydrogen atom abstraction from the substrate caused by [FeO](3+), (2) rotation of the OH group of the sixth ligand of [FeOH](3+) produced by process 1, (3) substrate radical binding with the [FeOH](3+), and (4) elimination of the oxygenated substrate formed at the sixth ligand binding site. The rate-determining step is process 1, hydrogen atom abstraction from the substrate, and the activation energy was determined to be about 15 kcal/mol. For this reason, it is thought that this reaction occurs in vivo.

MeSH terms

  • Binding Sites
  • Camphor 5-Monooxygenase / chemistry
  • Camphor 5-Monooxygenase / metabolism
  • Catalysis
  • Cytochrome P-450 Enzyme System / chemistry*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Ferric Compounds / chemistry
  • Ferric Compounds / metabolism
  • Heme / chemistry
  • Hydroxylation
  • Models, Chemical
  • Molecular Conformation
  • Proteins / chemistry
  • Proteins / metabolism
  • Protoporphyrins / chemistry
  • Protoporphyrins / metabolism
  • Pseudomonas putida
  • Substrate Specificity


  • Ferric Compounds
  • Proteins
  • Protoporphyrins
  • Heme
  • Cytochrome P-450 Enzyme System
  • Camphor 5-Monooxygenase