Year: 2025
Type: article
Abstract: Biosynthesis of all androgens and estrogens from cholesterol requires CYP11A1 and CYP17A1. There is no known pathway in humans or other vertebrates that circumvents CYP17A1 for androgen or estrogen biosynthesis in physiology or disease. However, CYP17A1 inhibition cannot completely inhibit androgen biosynthesis in prostate cancer. Here, we identify a surprising role for CYP51 in androgen biosynthesis that bypasses the requirement for CYP17A1. We find that an oxysterol is converted to androgens, which we confirmed with synthesis of a deuterium-labeled oxysterol precursor. Of 57 human cytochrome P450 enzymes tested, only CYP51A1 is capable of circumventing CYP17A1. Genetic studies using stable isotope tracing demonstrate that CYP51A1 is essential for biosynthesis of 13C-testosterone from 13C-cholesterol. Other vertebrate orthologs of human CYP51A1 also synthesize androgens. CYP51A1 knockout suppressed androgen-regulated genes in vitro and in vivo in prostate cancer xenografts. These findings have broad implications for sex steroid physiology and pharmacologic therapies for steroid-dependent diseases. Biosynthesis of all androgens from cholesterol first requires cytochrome P450 (CYP) 11A1 for generation of pregnanes and then CYP17A1 for biosynthesis of androgens, but CYP17A1 inhibition cannot completely inhibit androgen biosynthesis in prostate cancer. Here, the authors identify a role for CYP51A1 in the biosynthesis of androgens that completely bypasses the requirement for CYP17A1 and demonstrate that CYP51A1 is essential for the biosynthesis of 13C-testosterone from 13C-cholesterol in prostate cancer cells.
Source: Nature Communications
Authors: Ziqi Zhu., Yoon-Mi Chung., Mohammad Alyamani., Yijing Dai., Kevin D., Roberts Evan McCarty, Evan Roberts, Sunita Sinha, Jianneng Li, Xiuxiu Li, Emad M., Zhou Zhiqun Gad, Zhiqun Zhou, Jinyuan Shi, Robert A., Y. Tatiana Burgess, Tatiana Y., I. Galina Hargrove, Galina I., Peter F Lepesheva, F Peter, J. Guengerich Richard, Sharifi Auchus Nima
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G128577082, G1441686131, Structural requirements for sterol 14α-demethylases, G2151190991, G2298622969, Elucidating a novel molecular biomarker for castration-resistant prostate cancer, G2817920880, G2998219133, G3419030034, G3911751649, Interactions of Androgen Production, Uptake and Metabolism on outcome in Castration Resistant Prostate Cancer, G427533880, G4460655905, G4870427513, Graduate Research Fellowship Program (GRFP), Functional Roles of Human Cytochrome P450 Enzymes, G648660745, G696970457, G8479742151, CYP17A1-independent androgen synthesis and prostate cancer resistance to next-generation hormonal therapy, G9000038791, G9000140840, G9000200567, G9000303975, Activation of androgen biosynthesis and drug metabolism by cytochrome b5
OpenAlex ID: W4416983934