Restoration of mutant cytochrome P450 reductase activity by external flavin

Nicolo, Catherine; Flück, Christa E; Mullis, Primus E; Pandey, Amit V (2010). Restoration of mutant cytochrome P450 reductase activity by external flavin. Molecular and cellular endocrinology, 321(2), pp. 245-52. Shannon: Elsevier Ireland 10.1016/j.mce.2010.02.024

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Cytochrome P450 oxidoreductase (POR) supplies electrons from NADPH to steroid and drug metabolizing reactions catalyzed by the cytochrome P450s located in endoplasmic reticulum. Mutations in human POR cause a wide spectrum of disease ranging from disordered steroidogenesis to sexual differentiation. Previously we and others have shown that POR mutations can lead to reduced activities of steroidogenic P450s CYP17A1, CYP19A1 and CYP21A1. Here we are reporting that mutations in the FMN binding domain of POR may reduce CYP3A4 activity, potentially influencing drug and steroid metabolism; and the loss of CYP3A4 activity may be correlated to the reduction of cytochrome b(5) by POR. Computational molecular docking experiments with a FMN free structural model of POR revealed that an external FMN could be docked in close proximity to the FAD moiety and receive electrons donated by NADPH. Using FMN supplemented assays we have demonstrated restoration of the defective POR activity in vitro.

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

UniBE Contributor:

Nicolo, Catherine; Flück, Christa; Mullis, Primus-Eugen and Pandey, Amit Vikram

ISSN:

0303-7207

Publisher:

Elsevier Ireland

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:07

Last Modified:

06 Dec 2013 13:19

Publisher DOI:

10.1016/j.mce.2010.02.024

PubMed ID:

20188793

Web of Science ID:

000277919000016

URI:

https://boris.unibe.ch/id/eprint/158 (FactScience: 196583)

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