Bioinformatic insight into the unity and diversity of cytochromes P450.
For the past few decades, cytochromes P450 (CYPs) have been the subject of extensive research, owing to the ability of these enzymes to serve as drug targets as well as to their active participation in drug metabolism. Other varieties and functions of CYPs have been discovered and this superfamily currently comprises over 2000 different protein species. In the present study, the protein sequences of CYPs were submitted to computer analysis for elucidation of the structural basis of their pronounced functional diversity. The basic local alignment search tool (BLAST) was used to demonstrate that CYP protein sequences share a certain general similarity; at the same time, it was shown that the CYP superfamily may be split into a number of groups of intimately related proteins. These groups, the families, were revealed by means of cluster analysis, which demonstrated a strong hierarchy among the animal, bacterial and fungal P450s, and the lack of such a hierarchy for plant enzymes. Multiple alignment and consensus sequence analysis were the approaches taken to find out which structural peculiarities of P450s are responsible for the deviations from the random picture. Proteins within each family were aligned and collapsed to the corresponding consensus sequences, the alignment of which produced the consensus for the whole superfamily. The latter consensus yielded a number of unity motifs (most of which being related to the heme-fixing assembly), while the cross-family comparison of consensus sequences enabled the retrieval of some diversity motifs. Three consensus sequences (for the CYP51 and CYP2 families and for the superfamily) were compared, to line up the unity and diversity motifs with the appropriate X-ray data.
Lisitsa
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Institute of Biomedical Chemistry RAMS, 119121 Moscow, Russia. fox@ibmh.msk.su
Archakov
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Lewi
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Janssen
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D000595:Amino Acid Sequence; D000818:Animals; D019295:Computational Biology / Q000379:methods*; D016384:Consensus Sequence; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D019143:Evolution, Molecular; D006801:Humans; D005810:Multigene Family; D013329:Structure-Activity Relationship
D003577:Cytochrome P-450 Enzyme System