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Microsomal 17alpha-hydroxylase/17,20-lyase cytochrome P450 (P450c17) catalyzes both the 17alpha-hydroxylase reaction required to produce cortisol, the major glucocorticoid in many animals, and the 17, 20-lyase activity required for the production of androgens in all animals. In rodents such as rat, which utilize 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 and gonads and participates in both glucocorticoid and androgen production. Rat and human forms of P450c17 are 69% identical at the amino acid level. Based on the differences in physiological roles between P450c17 in these two species, it could be predicted that major differences would be observed in their hydroxylase activities. Contrary to this hypothesis, using partially purified, recombinant human and rat P450c17, we found that the most significant differences lie in their lyase activities. Lyase activities demonstrate that the rat enzyme favors Delta4 (progesterone) substrates while the human enzyme favors Delta5 (pregnenolone) substrates. This substrate preference is also observed in the ability of steroids to decrease uncoupled H2O2 production and to increase stability during turnover. Cytochrome b5, a microsomal electron-transfer protein, enhances lyase activities of rat and human P450c17. However, the most dramatic stimulatory effect is on the human HO-PROG lyase activity. This enhancement of activities is not associated with electron transfer. These differences in biochemical properties between the two forms of P450c17 indicate that human P450c17 has evolved as an enzyme system that limits androgen production to the gonads where a favorable b5:P450c17 ratio exists. Even though orthologous forms of P450c17 are capable of catalyzing the same enzymatic activities, specific physiological requirements of each species ensure biochemical differences between these enzymes.