A bypass gateway from cholesterol to sex steroid biosynthesis circumnavigates CYP17A1
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 <sup>13</sup>C-testosterone from <sup>13</sup>C-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.
Authors
- Evan Roberts (ORCID: https://orcid.org/0000-0001-5621-4823)
- Sunita Sinha (ORCID: https://orcid.org/0000-0002-6576-2407)
- Mohammad Alyamani (ORCID: https://orcid.org/0000-0002-7127-0820)
- Jianneng Li (ORCID: https://orcid.org/0000-0001-7642-625X)
- Nima Sharifi (ORCID: https://orcid.org/0000-0003-1281-3474)
- Kevin D. McCarty (ORCID: https://orcid.org/0000-0003-0027-9120)
- Jinyuan Shi (ORCID: https://orcid.org/0000-0002-1183-8525)
- Galina I. Lepesheva (ORCID: https://orcid.org/0000-0002-6975-1131)
- Richard Joseph Auchus (ORCID: https://orcid.org/0000-0001-6815-6181)
- F. Peter Guengerich (ORCID: https://orcid.org/0000-0002-7458-3048)
- Emad M. Gad (ORCID: https://orcid.org/0000-0002-7220-2002)
- Zhiqun Zhou (ORCID: https://orcid.org/0000-0001-5248-8931)
- Ziqi Zhu (ORCID: https://orcid.org/0000-0001-8066-2052)
- Tatiana Y. Hargrove
- Xiuxiu Li (ORCID: https://orcid.org/0009-0003-7525-1672)
- Yuqiong Dai
- Yoon-Mi Chung
- Robert A. Burgess
Institutions
- University of Notre Dame (US)
- University of Miami (US)
- Pfizer (United States) (US)
- Vanderbilt University (US)
- Veterans Health Administration (US)
- Michigan Medicine (US)
- Miami Transplant Institute (US)
- Sylvester Comprehensive Cancer Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-04
- DOI
- https://doi.org/10.1038/s41467-025-66558-2
- Citations
- 2
- Primary Topic
- Estrogen and related hormone effects
- Type
- article
- Field-Weighted Citation Impact
- 3.63
Funders
- National Science Foundation
- Prostate Cancer Foundation
- National Institutes of Health
- National Cancer Institute