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Monooxygenase, Peroxidase and Peroxygenase Properties and Reaction Mechanisms of Cytochrome P450 Enzymes

  • Eugene G. HrycayEmail author
  • Stelvio M. Bandiera
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 851)

Abstract

This review examines the monooxygenase, peroxidase and peroxygenase properties and reaction mechanisms of cytochrome P450 (CYP) enzymes in bacterial, archaeal and mammalian systems. CYP enzymes catalyze monooxygenation reactions by inserting one oxygen atom from O2 into an enormous number and variety of substrates. The catalytic versatility of CYP stems from its ability to functionalize unactivated carbon-hydrogen (C−H) bonds of substrates through monooxygenation. The oxidative prowess of CYP in catalyzing monooxygenation reactions is attributed primarily to a porphyrin π radical ferryl intermediate known as Compound I (CpdI) (Por•+FeIV=O), or its ferryl radical resonance form (FeIV−O). CYP-mediated hydroxylations occur via a consensus H atom abstraction/oxygen rebound mechanism involving an initial abstraction by CpdI of a H atom from the substrate, generating a highly-reactive protonated Compound II (CpdII) intermediate (FeIV−OH) and a carbon-centered alkyl radical that rebounds onto the ferryl hydroxyl moiety to yield the hydroxylated substrate. CYP enzymes utilize hydroperoxides, peracids, perborate, percarbonate, periodate, chlorite, iodosobenzene and N-oxides as surrogate oxygen atom donors to oxygenate substrates via the shunt pathway in the absence of NAD(P)H/O2 and reduction-oxidation (redox) auxiliary proteins. It has been difficult to isolate the historically elusive CpdI intermediate in the native NAD(P)H/O2-supported monooxygenase pathway and to determine its precise electronic structure and kinetic and physicochemical properties because of its high reactivity, unstable nature (t ½ ~2 ms) and short life cycle, prompting suggestions for participation in monooxygenation reactions of alternative CYP iron-oxygen intermediates such as the ferric-peroxo anion species (FeIII−OO), ferric-hydroperoxo species (FeIII−OOH) and FeIII−(H2O2) complex.

Keywords

Cytochrome P450 Compound I Monooxygenase Peroxygenase Peroxide shunt Reaction mechanisms CYP protein engineering 

Notes

Acknowledgments

The authors acknowledge current and previous support from the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research.

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Faculty of Pharmaceutical SciencesThe University of British ColumbiaVancouverCanada

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