Evolution of the cytochrome P450 superfamily: sequence alignments and pharmacogenetics
Introduction
The cytochromes P450 (CYP) comprise a superfamily of heme-thiolate enzymes, of which 504 or more individual members have been identified and sequenced, that are primarily associated with the Phase 1 oxygenation of organic compounds, both exogenous and endogenous, in all species investigated thus far, including those of: bacteria, fungi, plants, fish, birds, reptiles, insects and mammalia, including man 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. The general reaction for P450-mediated mono-oxygenation of a hydrocarbon-based substrate, RH, can be represented as follows:where molecular dioxygen is cleaved by the sequential input of two reducing equivalents, supplied by NADPH or NADH, whereupon a single oxygen atom is inserted into the substrate to produce an oxygenated metabolite, ROH, with concomitant generation of water from the second oxygen atom.
P450 isozymes are able to catalyze a considerable variety of oxidations for many structural classes of chemicals, and it has been estimated that the total number of P450 substrates may exceed 200,000 which would include the majority of drugs and other xenobiotics, together with several types of endobiotics such as: steroids, fatty acids, eicosanoids, retinoids and prostaglandins. Although P450s are largely encountered in aerobic organisms, it is possible that they could have origins in anaerobic bacterial species which developed when the earth possessed a reducing atmosphere, but may have, nevertheless, contained sufficient oxygen concentrations to support mixed function oxidase activity generally associated with P450 catalysis. Consequently, since the origin of terrestrial life at around 3850 million years ago [13] it has been estimated that P450 emerged in an ancestral prokaryotic species as early as 3500 million years ago [1].
Section snippets
P450 phylogenetic trees
Over the last ten years or more successive compilations of reported P450 sequences have shown a dramatic increase in known P450 isozymes, and Fig. 1 demonstrates that the number of sequenced P450s published displays an exponential rise, suggesting that many more P450 genes are likely to be characterized in future. Currently, the number of P450s known from cDNA and other sequencing procedures has been reported to be 481, according to the most recent update [2], and is likely to be over 500
Comparison between P450 phylogeny and evolution of species
The generally accepted timescale for the development of biota [29] is summarized in Table 1, which provides a convenient point of comparison with the P450 phylogenetic tree. It is thought that the earliest forms of life were anaerobic bacteria which appeared around 3800 million years ago [13], and the change from an originally reducing atmosphere to an oxidising one occurred about 2000 million years ago, as the evolution of photosynthetic systems gave rise to a steady increase in atmospheric
Genetic polymorphism and pharmacogenetics
Human cytochromes P450 are known to be subject to a certain degree of genetic variation. In particular, there is clear evidence for impaired metabolic functions relating to CYP2D6 and CYP2C19 isoforms in relatively small percentages of certain ethnogeographical populations, whereas similar examples of genetic polymorphism arising from allelic variants in P450 genes are suspected for CYP1A1, CYP1A2, CYP2A6 and CYP2E1 [70]. It is possible that all human P450s are subject to inter-individual
Species differences in metabolism
Although a substantial number of both endogenous and exogenous P450 substrates are metabolized similarly by mammalian species, there are also examples where differences occur which may be due to either the same chemical being metabolized by different isoforms or by orthologous P450s within the same family/subfamily. For example, phenobarbital treatment increases the toxicity of paracetamol (acetamidophen) in rat and mouse, but decreases the toxicity of this chemical in the hamster [91].
Sequence alignments and P450 models
One method for rationalizing P450 substrate specificity and species differences in metabolism is to construct molecular models of either the putative active sites 97, 98, 99 or of the entire P450 enzymes of relevance 8, 100, 101, 102, 103, 104. In order to accomplish this one requires a relatively homologous P450 crystal structure, as a starting template, and a means of carrying out the molecular mutagenesis of the relevant amino acid residues identified by protein sequence alignment of the
Acknowledgements
The financial support of GlaxoWellcome, Merck, Sharp and Dohme, and the University of Surrey Foundation Fund is gratefully acknowledged by one of us (DFVL).
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