STRUCTURAL AND EVOLUTIONARY STUDIES ON STEROL 14-DEMETHYLASE P450 (CYP51), THE MOST CONSERVED P450 MONOOXYGENASE .2. EVOLUTIONARY ANALYSIS OF PROTEIN AND GENE STRUCTURES

Phylogenetic analyses based on protein sequence data indicated that st erol 14-demethylase P450 (CYP51) and bacterial CYP51-like protein were joined into a distinctive evolutionary cluster, CYP51 cluster, within the CYP protein superfamily. The most probable branch topology of the CYP51 phylogenetic tree was (bacteria, (plants, (fungi, mammals))), w hich is comparable to the phylogeny of major kingdoms of living matter , suggesting that CYP51 has been conserved from the era of prokaryotic evolution, This may be strong evidence supporting the prokaryotic ori gin of P450. Structure of flanking regions and the number and insertio n sites of introns are quite different between mammalian and fungal CY P51s. This fact indicates that different mechanisms are operative in e volution of protein sequences and gene structures. CYP51 is the first example violating the well-documented rule that the basic structure of a gene, including intron insertion sites, is well conserved in each P 450 family. One CYP51 processed a pseudogene was found in rat genome, Nonsynonymous nucleotide divergence observed between the pseudogene an d CYP51 cDNA was less than one-fifth of the synonymous divergence, Thi s unusually low rate of nonsynonymous nucleotide changes in the pseudo gene suggests that it may be derived from another CYP51, which might h ave been active for a significant duration in the past.