Human cytochrome P450 17A1 structures with metabolites of prostate cancer drug abiraterone reveal substrate-binding plasticity and a second binding site.

ABSTRACT: Abiraterone acetate is a first-line therapy for castration-resistant prostate cancer. This prodrug is deacetylated in vivo to abiraterone, which is a potent and specific inhibitor of cytochrome P450 17A1 (CYP17A1). CYP17A1 performs two sequential steps that are required for the biosynthesis of androgens that drive prostate cancer proliferation, analogous to estrogens in breast cancer. Abiraterone can be further metabolized in vivo on the steroid A ring to multiple metabolites that also inhibit CYP17A1. Despite its design as an active-site-directed substrate analog, abiraterone and its metabolites demonstrate mixed competitive/noncompetitive inhibition. To understand their binding, we solved the X-ray structures of CYP17A1 with three primary abiraterone metabolites. Despite different confor

SUBMITTER: Petrunak EM 

PROVIDER: S-EPMC10023946 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature