Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome.

TLDR

Microsomal cytochrome P450c17 catalyzes both 17α‑hydroxylase and 17,20‑lyase reactions, with the latter’s activity regulated independently in a complex, age‑dependent manner. The study investigates whether hormonally regulated serine phosphorylation of P450c17 provides a mechanism for adrenarche and links hyperandrogenism to insulin resistance in polycystic ovary syndrome. Phosphorylation of P450c17 on serine and threonine residues by cAMP‑dependent protein kinase boosts 17,20‑lyase activity, while dephosphorylation abolishes it.

Abstract

Microsomal cytochrome P450c17 catalyzes both steroid 17 alpha-hydroxylase activity and scission of the C17-C20 steroid bond (17,20-lyase) on the same active site. Adrenal 17 alpha-hydroxylase activity is needed to produce cortisol throughout life, but 17,20-lyase activity appears to be controlled independently in a complex, age-dependent pattern. We show that human P450c17 is phosphorylated on serine and threonine residues by a cAMP-dependent protein kinase. Phosphorylation of P450c17 increases 17,20-lyase activity, while dephosphorylation virtually eliminates this activity. Hormonally regulated serine phosphorylation of human P450c17 suggests a possible mechanism for human adrenarche and may be a unifying etiologic link between the hyperandrogenism and insulin resistance that characterize the polycystic ovary syndrome.