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Monooxygenase, Peroxidase and Peroxygenase Properties and Mechanisms of Cytochrome P450 pp 1–61Cite as

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

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Part of the book series: Advances in Experimental Medicine and Biology ((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.

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Notes

  1. 1.

    Abbreviations: AaeUPO Agrocybe aegerita unspecific peroxygenase, CcP cytochrome c peroxidase, mCPBA m-chloroperbenzoic acid, CpdI Compound I, CpdII Compound II, Cpd0 Compound Zero, CpdES Compound ES, CPO chloroperoxidase, CPR NADPH-cytochrome P450 oxidoreductase, CYP cytochrome P450, HRP horseradish peroxidase, KIEs kinetic isotope effects, PGG 2 9α,11α-epidioxy-15S-hydroperoxyprosta-5Z,13E-dien-1-oic acid, PGH 2 9α,11α-epidioxy-15S-hydroxyprosta-5Z,13E-dien-1-oic acid, TMPD N,N,N′,N′-tetramethyl-p-phenylenediamine. Amino acid abbreviations: Ala alanine, Arg arginine, Asn asparagine, Asp aspartic acid, Cys cysteine, Glu glutamic acid, Gly glycine, His histidine, Ile isoleucine, Leu leucine, Lys lysine, Met methionine, Phe phenylalanine, Pro proline, Ser serine, Thr threonine, Trp tryptophan, Tyr tyrosine, Val valine.

  2. 2.

    Members of the CYP superfamily are called enzymes and should not be referred to as isoforms or iso(en)zymes. All CYP members are different enzymes and are products of different genes of the CYP superfamily (Dr. R. Feyereisen, CNRS, Univ. Nice Sophia Antipolis, France, personal communication).

  3. 3.

    A review of this scope cannot include all references pertaining to the subject matter presented.

  4. 4.

    The number of discovered CYP members in the archaeal kingdom as of April 21st, 2011 was 39, and was obtained through a BLAST search of the reference protein sequence database of the NCBI [371].

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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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  1. Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia, V6T1Z3, Canada

    Eugene G. Hrycay & Stelvio M. Bandiera

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  1. Eugene G. Hrycay
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Correspondence to Eugene G. Hrycay .

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    Eugene G. Hrycay

  2. Fac. of Pharmaceutical Sciences, The University of British Columbia , Vancouver, British Columbia, Canada

    Stelvio M. Bandiera

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Hrycay, E.G., Bandiera, S.M. (2015). Monooxygenase, Peroxidase and Peroxygenase Properties and Reaction Mechanisms of Cytochrome P450 Enzymes. In: Hrycay, E., Bandiera, S. (eds) Monooxygenase, Peroxidase and Peroxygenase Properties and Mechanisms of Cytochrome P450. Advances in Experimental Medicine and Biology, vol 851. Springer, Cham. https://doi.org/10.1007/978-3-319-16009-2_1

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