| Abstract
| - Microsomal 17α-hydroxylase/17,20-lyase cytochrome P450 (P450c17) catalyzes both the 17α-hydroxylase reaction required to produce cortisol, the major glucocorticoid in many animals, and the17,20-lyase activity required for the production of androgens in all animals. In rodents such as rat, whichutilize corticosterone as the major glucocorticoid, P450c17 is expressed predominantly in the gonads,and is absent in the adrenal. In other species including humans, P450c17 is expressed in both adrenal andgonads and participates in both glucocorticoid and androgen production. Rat and human forms of P450c17are 69% identical at the amino acid level. Based on the differences in physiological roles between P450c17in these two species, it could be predicted that major differences would be observed in their hydroxylaseactivities. Contrary to this hypothesis, using partially purified, recombinant human and rat P450c17, wefound that the most significant differences lie in their lyase activities. Lyase activities demonstrate thatthe rat enzyme favors Δ4 (progesterone) substrates while the human enzyme favors Δ5 (pregnenolone)substrates. This substrate preference is also observed in the ability of steroids to decrease uncoupledH2O2 production and to increase stability during turnover. Cytochrome b5, a microsomal electron-transferprotein, enhances lyase activities of rat and human P450c17. However, the most dramatic stimulatoryeffect is on the human HO-PROG lyase activity. This enhancement of activities is not associated withelectron transfer. These differences in biochemical properties between the two forms of P450c17 indicatethat human P450c17 has evolved as an enzyme system that limits androgen production to the gonadswhere a favorable b5:P450c17 ratio exists. Even though orthologous forms of P450c17 are capable ofcatalyzing the same enzymatic activities, specific physiological requirements of each species ensurebiochemical differences between these enzymes.
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