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Oxidizing Intermediates in P450 Catalysis: A Case for Multiple Oxidants

  • Chapter
Monooxygenase, Peroxidase and Peroxygenase Properties and Mechanisms of Cytochrome P450

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 851))

Abstract

Cytochrome P450 (P450 or CYP) catalysis involves the oxygenation of organic compounds via a series of catalytic intermediates, namely, the ferric-peroxo, ferric-hydroperoxo, Compound I (Cpd I) and FeIII−(H2O2) intermediates. Now that the structures of P450 enzymes have been well established, a major focus of current research in the P450 area has been unraveling the intimate details and activities of these reactive intermediates. The general consensus is that the Cpd I intermediate is the most reactive species in the reaction cycle, especially when the reaction involves hydrocarbon hydroxylation. Cpd I has recently been characterized experimentally. Other than Cpd I, there is a multitude of evidence, both experimental as well as theoretical, supporting the involvement of other intermediates in various types of oxidation reactions. The involvement of these multiple oxidants has been experimentally demonstrated using P450 active-site mutants in epoxidation, heteroatom oxidation and dealkylation reactions. In this chapter, we will review the P450 reaction cycle and each of the reactive intermediates to discuss their role in oxidation reactions.

Abbreviations: Cpd I or Cpd II compound I or II of a heme enzyme, an FeIV=O radical cation species, CPO chloroperoxidase, CYP or P450 cytochrome P450, CYP119A1 orphan P450 from Sulfolobus acidocaldarius, CYP2B4 phenobarbital-inducible rabbit liver microsomal P450 enzyme (P450LM2), CYP2E1 alcohol-inducible rabbit liver microsomal P450 enzyme (P450LM3), CYP51A1 lanosterol 14α-demethylase, ENDOR electron-nuclear double resonance, EPR electron paramagnetic resonance, ES enzyme-substrate complex, FAD flavin adenine dinucleotide, FMN flavin mononucleotide, heme iron protoporphyrin IX (heme-b), KIE kinetic isotope effect, NOS nitric oxide synthase enzyme, P450BM3 fatty acid hydroxylating P450 enzyme from Bacillus megaterium, P450CAM camphor-hydroxylating P450 enzyme from Pseudomonas putida, RH substrate, ROH oxidized substrate.

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Acknowledgment

The NIH (GM-26730) has supported cytochrome P450 research in the Dawson laboratory. We would like to thank Dr. Masanori Sono for pertinent advice.

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  1. Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, 29208, USA

    Anuja R. Modi & John H. Dawson

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  1. Anuja R. Modi
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Correspondence to John H. Dawson .

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  1. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada

    Eugene G. Hrycay

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

    Stelvio M. Bandiera

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Modi, A.R., Dawson, J.H. (2015). Oxidizing Intermediates in P450 Catalysis: A Case for Multiple Oxidants. 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_2

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