Genetic and structural analyses of cytochrome P450 hydroxylases in sex hormone biosynthesis: Sequential origin and subsequent coevolution

Abstract

Biosynthesis of steroid hormones in vertebrates involves three cytochrome P450 hydroxylases, CYP11A1, CYP17A1 and CYP19A1, which catalyze sequential steps in steroidogenesis. These enzymes are conserved in the vertebrates, but their origin and existence in other chordate subphyla (Tunicata and Cephalochordata) have not been clearly established. In this study, selected protein sequences of CYP11A1, CYP17A1 and CYP19A1 were compiled and analyzed using multiple sequence alignment and phylogenetic analysis. Our analyses show that cephalochordates have sequences orthologous to vertebrate CYP11A1, CYP17A1 or CYP19A1, and that echinoderms and hemichordates possess CYP11-like but not CYP19 genes. While the cephalochordate sequences have low identity with the vertebrate sequences, reflecting evolutionary distance, the data show apparent origin of CYP11 prior to the evolution of CYP19 and possibly CYP17, thus indicating a sequential origin of these functionally related steroidogenic CYPs. Co-occurrence of the three CYPs in early chordates suggests that the three genes may have coevolved thereafter, and that functional conservation should be reflected in functionally important residues in the proteins. CYP19A1 has the largest number of conserved residues while CYP11A1 sequences are less conserved. Structural analyses of human CYP11A1, CYP17A1 and CYP19A1 show that critical substrate binding site residues are highly conserved in each enzyme family. The results emphasize that the steroidogenic pathways producing glucocorticoids and reproductive steroids are several hundred million years old and that the catalytic structural elements of the enzymes have been conserved over the same period of time. Analysis of these elements may help to identify when precursor functions linked to these enzymes first arose.

Genome description and inventory of immune-related genes of the endangered pen shell Pinna nobilis: a giant bivalve experiencing a mass mortality event

“…Noteworthy, no CYP19, i.e. the aromatase, was identified which is also consistent with other reported observations in invertebrates [129,130].…”

Genetic biomarkers for hepatocellular cancer risk in a caucasian population

“…The CYP17A1 rs743572 (-34T>C) polymorphism was found to be a strong protective factor against HCC development in both the high-risk HCV/HBV-positive group and healthy individuals. CYP17A1 is an enzyme that plays a critical role in the biosynthesis of steroid hormones by catalyzing both 17a-hydroxylase and 17, 20-lyase activities[ 38 ]. Some data derived from animal models and human epidemiologic studies have demonstrated that estrogens play an essential role in hepatocarcinogenesis; however, the exact mechanism underlying the effect of estrogen levels on HCC development is currently controversial[ 39 ].…”

A novel PDZ domain-containing gene is essential for male sex differentiation and maintenance in yellow catfish (Pelteobagrus fulvidraco)

“…The Cyp19a1 gene encodes the enzyme aromatase that is responsible for converting androgens to estrogens [32]. Estrogen plays an important role in ovarian differentiation in fish species, since administration of estrogens can reverse genetic males to phenotypic females [33,34].…”