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Pharmaceuticals 2018, 11(2), 37; https://doi.org/10.3390/ph11020037

Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency

1
Growth and Development Research Unit, Vall d’Hebron Research Institute (VHIR), Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Autonomous University of Barcelona, Barcelona 08035, Spain
2
Pediatric Endocrinology Unit, Department of Paediatrics, University Children’s Hospital Bern, Bern 3010, Switzerland
3
Department of Biomedical Research, University of Bern, Bern 3010, Switzerland
4
Department of Nephrology and Hypertension, University of Bern, Bern 3010, Switzerland
5
Pediatric Service, Hospital Joan XXIII, Tarragona 43005, Spain
6
Pathology Department, Hospital Universitari Vall d’Hebron, CIBERER, Barcelona 08035, Spain
These authors contributed equally.
*
Author to whom correspondence should be addressed.
Received: 4 April 2018 / Revised: 23 April 2018 / Accepted: 25 April 2018 / Published: 29 April 2018
(This article belongs to the Special Issue Anticancer Drugs)
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Abstract

The CYP17A1 gene regulates sex steroid biosynthesis in humans through 17α-hydroxylase/17,20 lyase activities and is a target of anti-prostate cancer drug abiraterone. In a 46, XY patient with female external genitalia, together with a loss of function mutation S441P, we identified a novel missense mutation V366M at the catalytic center of CYP17A1 which preferentially impaired 17,20 lyase activity. Kinetic experiments with bacterially expressed proteins revealed that V366M mutant enzyme can bind and metabolize pregnenolone to 17OH-pregnenolone, but 17OH-pregnenolone binding and conversion to dehydroepiandrosterone (DHEA) was impaired, explaining the patient’s steroid profile. Abiraterone could not bind and inhibit the 17α-hydroxylase activity of the CYP17A1-V366M mutant. Molecular dynamics (MD) simulations showed that V366M creates a “one-way valve” and suggests a mechanism for dual activities of human CYP17A1 where, after the conversion of pregnenolone to 17OH-pregnenolone, the product exits the active site and re-enters for conversion to dehydroepiandrosterone. The V366M mutant also explained the effectiveness of the anti-prostate cancer drug abiraterone as a potent inhibitor of CYP17A1 by binding tightly at the active site in the WT enzyme. The V366M is the first human mutation to be described at the active site of CYP17A1 that causes isolated 17,20 lyase deficiency. Knowledge about the specificity of CYP17A1 activities is of importance for the development of treatments for polycystic ovary syndrome and inhibitors for prostate cancer therapy. View Full-Text
Keywords: P450c17; prostate cancer; abiraterone; steroidogenesis; androgens; dehydroepiandrosterone; CYP17A1; cytochrome P450; anti-cancer drugs; DSD P450c17; prostate cancer; abiraterone; steroidogenesis; androgens; dehydroepiandrosterone; CYP17A1; cytochrome P450; anti-cancer drugs; DSD
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Fernández-Cancio, M.; Camats, N.; Flück, C.E.; Zalewski, A.; Dick, B.; Frey, B.M.; Monné, R.; Torán, N.; Audí, L.; Pandey, A.V. Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency. Pharmaceuticals 2018, 11, 37.

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