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Cytochrome p450 enzymes in the generation of commercial products

Nature Reviews Drug Discovery volume 1, pages 359–366 (2002)Cite this article

Key Points

  • Cytochrome P450 (CYP) enzymes have been considered primarily in the context of drug metabolism as part of the development process, with the exceptions of fungal CYP51 (infections) and the aromatase CYP19 (hormonal cancers) as targets for inhibition.

  • Human CYPs are also potential targets in pathways that generate undesirable amounts of metabolites of endogenous chemicals as well as products of some carcinogenic xenobiotics.

  • An attractive use of CYPs is in the use of natural or randomly mutated CYPs to generate libraries of chemical metabolites for screening for use as drugs or other useful products.

  • Human CYPs can also be integrated into the discovery process, in terms of activating pro-drugs in the body.

  • Agricultural and associated applications include the use of CYPs in transgenic plants to alter resistance to pesticides, to generate products useful to the host plants and to generate colours or useful industrial products.

Abstract

Cytochrome P450 enzymes are remarkably diverse oxygenation catalysts that are found throughout nature. Although most of the interest in the pharmaceutical industry has focused on the role of cytochrome P450s in drug development, these enzymes also offer potential in the discovery not only of drugs, but also of other useful chemicals. Potential applications range from the use of cytochrome P450s as drug targets, to the use of randomly generated mutants of cytochrome P450s to produce libraries of new chemicals and drugs.

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Figure 1: Some reactions known to be catalysed by CYP enzymes.
Figure 2: Cytochrome P450 reactions used to synthesize drugs.
Figure 3: Strategy for random mutation of a hypothetical CYP gene in Streptomyces to discover new antibiotics.
Figure 4: CYP reactions with commercial potential.

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Acknowledgements

This work was supported in part by US Public Health Service grants.

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Authors and Affiliations

  1. Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, 37232-0146, Tennessee, USA

    F. Peter Guengerich

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  1. F. Peter Guengerich
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DATABASES

LocusLink

AH receptor

CDK5

CYP1B1

CYP2A6

CYP2E1

CYP3A4

CYP7A

CYP19

CYP51

GSK3

NADPH cytochrome P450 reductase

Medscape DrugInfo

cortisone

pravastatin

Taxol

FURTHER INFORMATION

Cytochrome P450 Homepage

Glossary

CYTOCHROME P450

A family of genes that encode haem proteins, which usually have monooxygenase catalytic activity. Abbreviated as 'CYP' (gene-family designation) or 'P450'. Humans have 55–60 CYP genes, and the number in other species varies from as few as 3 in Saccharomyces cerevisiae to nearly 300 in Arabodopsis thaliana. Bacteria, on the other hand, vary from having no CYP genes (Escherichia coli) to about 20 such genes (Mycobacterium tuberculosis).

XENOBIOTIC

A chemical that is found in the body due to exposure to substances not synthesized within or necessary to the body, including drugs.

ENDOGENOUS CHEMICAL

A chemical that is normally produced in the body, or is necessary for life and is usually present; for example, vitamins.

OXYGENASE

An enzyme that inserts one or two atoms of oxygen into a substrate (monoxygenases and dioxygenases, respectively). These processes are among the most common to be involved in the metabolism of both endogenous and xenobiotic chemicals.

BIOREMEDIATION

The use of organisms to remove pollutant chemicals.

RANDOM MUTAGENESIS

(Also referred to as 'directed evolution' or 'molecular breeding'.) The process of nonspecifically changing a gene (a CYP) in one or more codons to produce an uncharacterized mixture of mutated genes, followed by selection and screening for genes that yield products with a desired catalytic activity (or enhanced levels of the inherent function of the original gene).

LIBRARY

A large mixture of chemicals or genes, many of which might be uncharacterized, from which members with desired properties can be selected.

BIOSENSOR

A device that can detect specific molecules — in this case, drugs.

THERMOPHILES

Bacteria that live at high temperatures (usually from he Kingdom archaebacteria).

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Guengerich, F. Cytochrome p450 enzymes in the generation of commercial products. Nat Rev Drug Discov 1, 359–366 (2002). https://doi.org/10.1038/nrd792

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