Cytochromes P450 and drug discovery

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Cytochromes P450 (CYP) are a superfamily of haem-containing proteins distributed widely throughout nature. Historically, they have a central role in drug metabolism and following the advent of genomics they have been shown to have key roles in the biosynthesis of natural products which are used as medicines. Herein, we provide an overview of CYP systems with particular emphasis on their role as drug targets, their involvement in drug biosynthesis and potential strategies for developing new derivatives of drugs based on CYP engineering. The applied importance of CYPs for medicinal and biotechnological applications will also be discussed.

Introduction

Cytochromes P450 (CYP) comprise a superfamily of haem-containing enzymes which catalyze the molecular scission of atmospheric oxygen and are distributed across the kingdoms of life [1••]. New CYP sequences are being added to the current list of >6500 each day (http://drnelson.utmem.edu/CytochromeP450.html; http://p450.antibes.inra.fr; http://Arabidopsis-P450.biotec.uiuc.edu). CYP monooxygenases have pivotal roles in primary and secondary metabolic pathways. They have long been of interest because of their extraordinary ability to introduce atmospheric oxygen into non-activated carbon-hydrogen bonds, showing exceptionally high degrees of regio-selectivity and stereo-selectivity. In general, one oxygen atom is incorporated into the substrate molecule, usually a hydrocarbon, and the other oxygen atom is reduced to a water molecule. The basic CYP enzymatic reactions include C-hydroxylation, heteroatom oxygenation, heteroatom release (dealkylation), epoxide formation and group migration (Figure 1). However, in recent years a number of more complex CYP reactions have also been described and these include chlorine oxygenation, aromatic dehalogenation, dimer formation, ring coupling, ring formation, ring contraction and oxidative aryl migration (Figure 1; [2]). All CYPs use NAD(P)H as a source of electrons for the catalysis of dioxygen molecular scission and a redox partner(s) (usually NADPH cytochrome P450 reductase for eukaryotic CYPs and a ferredoxin and a ferredoxin reductase for prokaryotic CYPs) is required to transfer the reducing equivalents to the CYP haem Fe for catalysis.

The role of this review is to provide a summary of the most recent advances in our knowledge and application of CYPs in drug discovery. To this end, the review will summarize the roles of CYPs as drug targets as well as the roles they play in the biosynthesis of drugs (Figure 2). A very large body of information on the biology of mammalian CYPs in drug metabolism already exists and we direct the reader to the following article for expansive information in this area [3].

Section snippets

Current strategies for inhibiting CYPs for clinical application

Examples of the use of CYPs as drug targets are rare in medicine. Of the human CYPs, only CYP19A1 (aromatase) has a real status as a drug target. This is the enzyme that converts androgens to oestrogens, and inhibitors such as anastrozole, exemestane and letrozole (Figure 3a, [4]) have efficacy in oestrogen-dependent tumours (breast, endometrium). The primary drawback to the use of CYP19A1 inhibitors in clinical therapy is the problem of achieving direct specificity for tumours, in that CYP19A1

Exploitation of microbial CYPs in drug discovery

The genomic era has revealed that CYP enzymes catalyze a large proportion of the most complex and chemically challenging steps in the biosynthesis of many natural products used in medicine today. Given the diversity of reactions catalysed by CYPs, only a few examples exist in industry where CYP enzymes have been exploited. The history goes back at least 50 years, for example the conversion of progesterone to cortisone through 11α-hydroxylation by Rhizopus cultures [16]. Several pharmaceutical

Strategies for drug discovery involved CYP bioengineering

Historically, natural product research in drug discovery has been a process of pharmacognosy, that is searching various extracts of plants, soil bacteria, ocean extracts, among others. However, knowledge about biosynthetic pathways allows for new strategies.

Conclusions and future perspectives

CYP biodiversity is presenting an exciting opportunity both to screen pathogens containing CYPs to be potential drug targets and to dissect CYP function to reveal roles in drug biosynthesis which are then open to manipulation in the hope of generating new drugs. In particular new genome sequencing projects have revealed many CYPs linked to antibiotic producing gene clusters both from the terrestrial and aquatic environments and such information will provide solid foundations in the drug

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by National Institutes of Health Grants R01GM69970, R37 CA090426 and P30ES00267 and by a Leverhulme Trust Research Fellowship.

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