Substrate-Dependent Evolution of Cytochrome P450: Rapid Turnover of the Detoxification-Type and Conservation of the Biosynthesis-Type

Members of the cytochrome P450 family are important metabolic enzymes that are present in all metazoans. Genes encoding cytochrome P450s form a multi-gene family, and the number of genes varies widely among species. The enzymes are classified as either biosynthesis-or detoxification-type, depending on their substrates, but their origin and evolution have not been fully understood. In order to elucidate the birth and death process of cytochrome P450 genes, we performed a phylogenetic analysis of 710 sequences from 14 vertebrate genomes and 543 sequences from 6 invertebrate genomes. Our results showed that vertebrate detoxification-type genes have independently emerged three times from biosynthesis-type genes and that invertebrate detoxification-type genes differ from vertebrates in their origins. Biosynthetic-type genes exhibit more conserved evolutionary processes than do detoxification-type genes, with regard to the rate of gene duplication, pseudogenization, and amino acid substitution. The differences in the evolutionary mode between biosynthesis- and detoxification-type genes may reflect differences in their respective substrates. The phylogenetic tree also revealed 11 clans comprising an upper category to families in the cytochrome P450 nomenclature. Here, we report novel clan-specific amino acids that may be used for the qualitative definition of clans.