A bypass gateway from cholesterol to sex steroid biosynthesis circumnavigates CYP17A1

Ziqi Zhu, Yoon-Mi Chung, Mohammad Alyamani, Yijing Dai, Kevin D. McCarty, Evan Roberts, Sunita Sinha, Jianneng Li, Xiuxiu Li, Emad M. Gad, Zhiqun Zhou, Jinyuan Shi, Robert A. Burgess, Tatiana Y. Hargrove, Galina I. Lepesheva, F. Peter Guengerich, Richard J. Auchus and Nima Sharifi ()
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Ziqi Zhu: University of Miami Miller School of Medicine, Desai Sethi Urology Institute
Yoon-Mi Chung: University of Miami Miller School of Medicine, Desai Sethi Urology Institute
Mohammad Alyamani: University of Miami Miller School of Medicine, Desai Sethi Urology Institute
Yijing Dai: Pfizer
Kevin D. McCarty: Vanderbilt University School of Medicine, Department of Biochemistry
Evan Roberts: University of Miami Miller School of Medicine, Desai Sethi Urology Institute
Sunita Sinha: University of Miami Miller School of Medicine, Desai Sethi Urology Institute
Jianneng Li: University of Notre Dame, Department of Biological Sciences
Xiuxiu Li: University of Miami Miller School of Medicine, Desai Sethi Urology Institute
Emad M. Gad: University of Miami Miller School of Medicine, Desai Sethi Urology Institute
Zhiqun Zhou: University of Miami Miller School of Medicine, Desai Sethi Urology Institute
Jinyuan Shi: University of Miami Miller School of Medicine, Desai Sethi Urology Institute
Robert A. Burgess: University of Miami Miller School of Medicine, Desai Sethi Urology Institute
Tatiana Y. Hargrove: Vanderbilt University School of Medicine, Department of Biochemistry
Galina I. Lepesheva: Vanderbilt University School of Medicine, Department of Biochemistry
F. Peter Guengerich: Vanderbilt University School of Medicine, Department of Biochemistry
Richard J. Auchus: University of Michigan, Departments of Pharmacology & Internal Medicine, Division of Metabolism, Endocrinology and Diabetes
Nima Sharifi: University of Miami Miller School of Medicine, Desai Sethi Urology Institute

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-66558-2

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