Replacement of Natural Cofactors by Selected Hydrogen Peroxide Donors or Organic Peroxides Results in Improved Activity for CYP3A4 and CYP2D6

@article{Chefson2006ReplacementON,
  title={Replacement of Natural Cofactors by Selected Hydrogen Peroxide Donors or Organic Peroxides Results in Improved Activity for CYP3A4 and CYP2D6},
  author={Amandine Chefson and Jin Zhao and Karine Auclair},
  journal={ChemBioChem},
  year={2006},
  volume={7}
}
The cytochrome P450 enzymes (P450s or CYPs) form a ubiquitous family of heme proteins able to catalyze the monooxygenation of a wide range of substrates. P450s are of considerable interest in synthetic organic chemistry because of their impressive ability to catalyze the insertion of oxygen into nonactivated C H bonds. This useful reaction in organic chemistry has received much attention over several decades, but still remains a significant challenge. Some metal catalysts have been successfully… 
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References

SHOWING 1-10 OF 27 REFERENCES
Laboratory evolution of peroxide-mediated cytochrome P450 hydroxylation
TLDR
The directed evolution of the P450 from Pseudomonas putida is reported to create mutants that hydroxylate naphthalene in the absence of cofactors through the ‘peroxide shunt’ pathway, with more than 20-fold higher activity than the native enzyme.
A self-sufficient peroxide-driven hydroxylation biocatalyst.
TLDR
A self-sufficient P450 BM-3 variant which utilizes hydrogen peroxide (H2O2) to catalyze hydroxylation and epoxidation at high rates and offers an opportunity to employ cellfree P450 catalysis without requiring NAD(P)H regeneration, additional proteins, or dioxygen, and eliminates rate-limiting electron-transfer steps.
Regioselectivity and Activity of Cytochrome P450 BM‐3 and Mutant F87A in Reactions Driven by Hydrogen Peroxide
TLDR
While significantly enhancing peroxygenase activity, the F87A mutation also shifts hydroxylation further away from the terminal position, and the H2O2- driven reactions with either the full-length BM-3 enzyme or the heme domain are slow, but yield product distributions very similar to those generated when using NADPH and O2.
Engineering Cytochrome P450 BM-3 for Oxidation of Polycyclic Aromatic Hydrocarbons
TLDR
The high activities of the mutant towards polycyclic aromatic hydrocarbons indicate the potential of engineering P450 BM-3 for the biodegradation of these compounds in the environment.
Identification of the heme-modified peptides from cumene hydroperoxide-inactivated cytochrome P450 3A4.
TLDR
The incremental masses detected by electrospray mass spectrometric analyses of the heme-modified peptides are consistent with a dipyrrolic heme fragment comprised of either pyrrole ring A-D or B-C, a known soluble product of peroxidative heme degradation, as a modifying species.
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