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 (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Camats Tarruella, Núria (University of Bern)
Flück, Christa E. (University of Bern)
Zalewski, Adam (University of Bern)
Dick, Bernhard (Department of Nephrology and Hypertension)
Frey, Brigitte M. (University of Bern)
Monné, Raquel (Hospital Universitari Joan XXIII de Tarragona)
Torán, Núria (Hospital Universitari Vall d'Hebron)
Audí, Laura (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Pandey, Amit V. (University of Bern)
Universitat Autònoma de Barcelona

Data:	2018
Resum:	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.
Ajuts:	Agència de Gestió d'Ajuts Universitaris i de Recerca SGR05-00908 Agència de Gestió d'Ajuts Universitaris i de Recerca 2009SGR-31 Instituto de Salud Carlos III PI06/090
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	P450c17 ; Prostate cancer ; Abiraterone ; Steroidogenesis ; Androgens ; Dehydroepiandrosterone ; CYP17A1 ; Cytochrome P450 ; Anti-cancer drugs ; DSD
Publicat a:	Pharmaceuticals, Vol. 11 (april 2018) , ISSN 1424-8247

DOI: 10.3390/ph11020037
PMID: 29710837

24 p, 5.6 MB

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