THE REGULATION OF 17,20-LYASE ACTIVITY

P450c17 is a single microsomal enzyme that catalyzes two distinct ster oid biosynthetic activities: 17 alpha-hydroxylase and 17,20 lyase. Hum an beings have only one gene that encodes only one form of P450c17. Th ree clinical observations indicated that these were independently regu lated activities. First, several cases of isolated 17,20 lyase deficie ncy were reported, in which 17 alpha-hydroxylase activity was spared. Second, most adrenal steroidogenesis in children stops after 17 alpha- hydroxylation, thus permitting the synthesis of cortisol, whereas most gonadal steroidogenesis proceeds to C19 sex steroids as a result of b oth activities. Third, the 17,20 lyase activity of the human adrenal i s developmentally activated during adrenarche. To catalyze these two a ctivities, P450c17 must receive reducing equivalents from electron don ors (redox partners). Previous observations showed that the molar rati o of P450 oxidoreductase to P450c17 was 3-fold higher in the testis th an in the adrenal, and that increasing the molar ratio of the redox pa rtner to P450c17 would increase the ratio of 17,20 lyase activity to 1 7 alpha-hydroxylase. We have recently shown that P450c17 must be phosp horylated on serine and threonine residues by a cAMP-dependent protein kinase to acquire 17,20 lyase activity. We have also recently found t wo cases of isolated 17,20 lyase deficiency that have mutations of res idues in the proposed redox partner binding site. Together, these stud ies suggest a unified view of the regulation of 17,20 lyase activity. The ratio of 17,20 lyase to 17 alpha-hydroxylase activity of P450c17 i s regulated by the availability of reducing equivalents flowing to the enzyme. This can be increased the molar concentration of electron-don ating redox partners, such as P450 oxidoreductase or possibly cytochro me b(5), as appears to be the case in the gonads. Alternatively, the a ffinity of P450c17 for redox partners may be selectively increased by Ser/Thr phosphorylation, or selectively decreased by certain mutations in the redox partner binding site, in either case altering an electro static interaction between P450c17 and the redox partner. This model i s consistent with all present observations about the biochemistry, gen etics, enzymology, and clinical phenomenology of P450c17. (C) 1997 by Elsevier Science Inc.