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Oxygen Activation and Reactivity

  • Chapter
Cytochrome P450

Abstract

The cytochrome P450-catalyzed insertion of an oxygen into a substrate culminates a process that reduces molecular oxygen to a species equivalent, in terms of formal electron count and reactivity, to an oxygen atom.1–6 The cytochrome P450 catalytic cycle traverses the following steps (Fig. 1): (1) reversible substrate binding, (2) reduction of cytochrome P450 from the ferric to the ferrous state by auxiliary electron transport proteins, (3) binding of molecular oxygen to give the ferrous dioxygen complex, (4) transfer of a second electron from the auxiliary electron transport proteins, (5) cleavage of the oxygen-oxygen bond to give a molecule of water and an oxidizing species in which the second oxygen is bound to the iron, (6) insertion of the iron-bound oxygen into the substrate, and (7) product dissociation. In the case of microsomal cytochrome P450 enzymes, the auxiliary electron transport protein is cytochrome P450 reductase, although cytochrome b 5 is able in some instances to provide the second electron. In the case of most bacterial and mitochondrial cytochrome P450 enzymes the electron transfer partners are a flavoprotein (e.g., adrenodoxin reductase) and an iron-sulfur protein (e.g., adrenodoxin) (see Chapters 3 and 11). Uncoupling of catalytic turnover from substrate oxidation can divert the consumption of reducing equivalents toward the production of superoxide, H2O2, or water rather than substrate-derived products (see Chapter 3).6 Although the physiological turnover of cytochrome P450 generally adheres to the above sequence, alternative oxygen donors such as peroxides can react with cytochrome P450 via “shunt” mechanisms that produce the activated oxidizing species without recourse to reducing equivalents or molecular oxygen. The early parts of this catalytic cycle involving reductive activation of molecular oxygen are discussed in detail in Chapters 3 and 7. This chapter concentrates on the nature of the activated oxidizing species, the shunt pathways for its formation, and its reactions with organic substrates.

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  1. Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, San Francisco, California, 94143, USA

    Paul R. Ortiz de Montellano

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    Paul R. Ortiz de Montellano

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de Montellano, P.R.O. (1995). Oxygen Activation and Reactivity. In: de Montellano, P.R.O. (eds) Cytochrome P450. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-2391-5_8

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  • DOI: https://doi.org/10.1007/978-1-4757-2391-5_8

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