The 17, 20-lyase activity of cytochrome P450c17 from human fetal testis favors the Δ⁵ steroidogenic pathway

Abstract:

Cytochrome P450c17 catalyzes both 17α-hydroxylation and 17,20-lyase conversion of 21-carbon steroids to 19-carbon precursors of sex steroids. P450c17 can mediate testosterone biosynthesis via the conversion of pregnenolone to dehydroepiandrosterone (the Δ5 pathway) or via conversion of progesterone to androstenedione (the Δ4 pathway). In many species, the 17, 20-lyase activity of P450c17 for one pathway dominates, reflecting the preferred steroidogenic pathway of that species. All studies of recombinant human P450c17 and of human adrenal microsomes have found high 17, 20-lyase activity only in the Δ5 pathway. Because the 17, 20-lyase activities in both the Δ4 and Δ5 pathways for testicular P450c17 have not been directly compared, however, it is not known if the Δ5 pathway dominates in the human testis. To resolve this issue, we assayed the conversion of 17α-hydroxypregnenolone to dehydroepiandrosterone (Δ5 17, 20-lyase activity) and of 17α-hydroxyprogesterone to androstenedione (Δ4 17, 20-lyase activity) by human fetal testicular microsomes. We obtained apparent Michaelis constant (Km) and maximum velocity (Vmax) values of 1.0 μM and 0.73 pmol·min-1·μg -1 for Δ5 17, 20-lyase activity and of 3.5 μM and 0.23 pmol·min-1·μg-1 for Δ 4 17, 20-lyase activity. Catalytic efficiencies, expressed as the ratio Vmax/Km, were 0.73 and 0.066 for the Δ 5 and Δ4 reactions, respectively, indicating 11-fold higher preference for the Δ5 pathway. We conclude that the majority of testosterone biosynthesis in the human testis proceeds through the conversion of pregnenolone to dehydroepiandrosterone via the Δ 5 pathway.

Año de publicación:

2003

Keywords:

Fuente:

scopus