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Human Steroidogenic Cytochrome P45017A1: Roles of Key Active Site Residues

Cytochrome P450 17A1 (CYP17A1) is a monooxygenase required for the biosynthesis of androgens and estrogens, which promote prostate and breast cancer growth, respectively. A new approach is to inhibit CYP17A1. However, CYP17A1 performs not only the 17,20‐lyase reaction needed only for androgen/estrogen production, but also a 17α‐hydroxylation reaction important for the synthesis of androgens, estrogens, and glucocorticoids. CYP17A1 inhibitor drugs currently available block both reactions and have side effects due to disruption of glucocorticoid synthesis. Our goal is to investigate CYP17A1 enzyme function to facilitate the design of inhibitors that only block the lyase reaction. Based on new CYP17A1 structures, active site amino acids Y201, N202, D298, R239, E305, I371, and V482 are proposed to play key roles in catalysis. Site‐directed mutagenesis was used to examine the roles of each amino acid in binding substrate or the prostate cancer drug abiraterone. Results show that abiraterone still binds tightly without hydrogen bond interaction to N202. Evaluating the roles these amino acids play in ligand binding will help understand enzyme function and direct drug development. Future studies will focus on evaluating the roles these amino acids play in the enzymatic catalysis of progesterone and pregnenolone via hydroxylase and lyase reactions. Supported by NIH NIGMS (GM078441, GM103420) and NCRR (RR017708).