Review
Complex reactions catalyzed by cytochrome P450 enzymes

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Abstract

Cytochrome P450 (P450) enzymes are some of the most versatile redox proteins known. The basic P450 reactions include C-hydroxylation, heteroatom oxygenation, heteroatom release (dealkylation), and epoxide formation. Mechanistic explanations for these reactions have been advanced. A number of more complex P450 reactions also occur, and these can be understood largely in the context of the basic chemical mechanisms and subsequent rearrangements. The list discussed here updates a 2001 review and includes chlorine oxygenation, aromatic dehalogenation, formation of diindole products, dimer formation via Diels–Alder reactions of products, ring coupling and also ring formation, reductive activation (e.g., aristolochic acid), ring contraction (piperidine nitroxide radical), oxidation of troglitazone, cleavage of amino oxazoles and a 1,2,4-oxadiazole ring, bioactivation of a dihydrobenzoxathiin, and oxidative aryl migration.

Introduction

Cytochrome P450 (P450) enzymes are some of the most versatile redox proteins known. Collectively they use substrates ranging in size from ethylene (Mr 28) to cyclosporin A (Mr 1201). Some of the P450s are indispensable, being essential for normal development and homeostasis in mammalians or allowing microorganisms to live on particular carbon sources [1] or to produce compounds for defense [2], [3]. The so-called xenobiotic-metabolizing P450s are generally not considered to be individually critical for life but collectively serve as defense against the detrimental effects of natural products, e.g. alkaloids, terpenes that would accumulate and be harmful. The relatively low specificity of these P450s thus provides a general defense system, and this broad specificity carries over to drugs and other synthetic chemicals.

Section snippets

P450 catalytic mechanisms

The P450 catalytic cycle is usually considered in the general form shown in Fig. 1. The course of events follows the order of substrate binding, 1-electron reduction, O2 binding, a second 1-electron reduction, and then a series of less well-defined steps understood as protonation, homolytic scission of the O–O bond to yield an active perferryl FeO species (depicted as FeO3+), reaction with the substrate, and release of the product. The kinetics of these systems have been discussed elsewhere [4]

Simple P450 reactions and previously reviewed rearrangements

The basic P450 reactions include C-hydroxylation, heteroatom oxygenation, heteroatom release (dealkylation), epoxide formation, and 1,2-migration (Fig. 2) [11]. Mechanistic explanations for these reactions have been advanced, and a relatively high level of understanding is available [12], [13].

A number of more complex P450 reactions were reviewed in an article written in late 2000 [12]. For the sake of brevity, examples (or general descriptions) of each are shown in Fig. 3, along with a word

Chlorine oxygenation

As pointed out above, heteroatom oxygenation is a relatively well-documented P450 reaction [11], [13], [31], [32]. The P450-catalyzed oxygenation of halides had been proposed [33], [34] and demonstrated with iodine and possibly bromine [35]. Recently Ortiz de Montellano and his co-workers [36] provided clear evidence that P450 4A1 can catalyze the oxygenation of alkyl iodides, bromides, and chlorides (Fig. 4). The reaction with an alkyl chloride is somewhat surprising, in light of the lower

Conclusions

The examples presented here, along with earlier work (Fig. 3) [12], [13], [83], [84] show the diversity of oxidations that can occur in P450 reactions. The list is intended to be illustrative rather than comprehensive, and more interesting chemistry will undoubtedly follow. Plant and microbial systems will be interesting sources for reactions, as will the pharmaceutical industry.

Most of the reactions described here can be rationalized with FeO3+-based mechanisms, with a few exceptions where

Acknowledgments

This work was supported in part by United States Public Health Service Grants R37 CA090426 and P30 ES00267. We thank K. Trisler for assistance in preparation of the manuscript.

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