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.