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

Fernández-Cancio, Mónica; Camats Tarruella, Núria; Flück Pandey, Christa Emma; Zalewski, Adam; Dick, Bernhard; Frey, Brigitte; Monné, Raquel; Torán, Núria; Audí, Laura; Pandey, Amit Vikram (2018). 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, 11(2), p. 37. MDPI 10.3390/ph11020037

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Endokrinologie / Diabetologie / Metabolik (Pädiatrie)
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension

UniBE Contributor:

Camats Tarruella, Núria; Flück Pandey, Christa Emma; Dick, Bernhard; Frey, Brigitte and Pandey, Amit Vikram

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1424-8247

Publisher:

MDPI

Funders:

[4] Swiss National Science Foundation
[UNSPECIFIED] Burgergemiende Bern
[UNSPECIFIED] Novartis Stiftung

Projects:

[104] Studies on human drug and steroid metabolism

Language:

English

Submitter:

Amit Vikram Pandey

Date Deposited:

09 May 2018 12:16

Last Modified:

22 Oct 2019 19:04

Publisher DOI:

10.3390/ph11020037

PubMed ID:

29710837

Uncontrolled Keywords:

P450c17; prostate cancer; abiraterone; steroidogenesis; androgens; dehydroepiandrosterone; CYP17A1; cytochrome P450; anti-cancer drugs; DSD

BORIS DOI:

10.7892/boris.116243

URI:

https://boris.unibe.ch/id/eprint/116243

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