Impact on CYP19A1 activity by mutations in NADPH cytochrome P450 oxidoreductase.

Flück Pandey, Christa Emma; Pandey, Amit Vikram (2017). Impact on CYP19A1 activity by mutations in NADPH cytochrome P450 oxidoreductase. Journal of steroid biochemistry and molecular biology, 165(Pt A), pp. 64-70. Elsevier 10.1016/j.jsbmb.2016.03.031

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Cytochrome P450 aromatase (CYP19A1), in human placenta metabolizes androgens to estrogens and uses reduced nicotinamide adenine dinucleotide phosphate through cytochrome P450 oxidoreductase (POR) for the energy requirements of its metabolic activities. Mutations in the human POR lead to congenital adrenal hyperplasia due to loss of activities of several steroid metabolizing enzymatic reactions conducted by the cytochrome P450 proteins located in the endoplasmic reticulum. Effect of POR mutations on different P450 activities depend on individual partner proteins. In this report we have studied the impact of mutations found in the POR on the enzymatic activity of CYP19A1. We expressed wild type as well mutant human POR proteins in bacteria and purified the recombinant proteins, which were then used in an in vitro reconstitution system in combination with CYP19A1 and lipids for enzymatic analysis. We found that several mutations as well as polymorphisms in human POR can cause reduction of CYP19A1 activity. This would affect metabolism of estrogens in people with variations of POR allele. The POR mutants Y181D and R616X were found to have no activity in supporting CYP19A1 reactions. The POR mutations Y607C and delF646 showed a loss of 60-90% activity and two polymorphic forms of POR, R316W and G413S showed similar to WT activity. One POR variant, Q153R had almost double the activity of WT. Loss of CYP19A1 activity may contribute to disordered steroidogenesis in female patients with POR mutations as well as in mothers with POR variants carrying a male child.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE)
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Other Institutions > Teaching Staff, Faculty of Medicine
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 > Endocrinology/Metabolic Disorders

UniBE Contributor:

Flück Pandey, Christa Emma and Pandey, Amit Vikram

Subjects:

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

ISSN:

0960-0760

Publisher:

Elsevier

Funders:

[4] Swiss National Science Foundation

Projects:

[102] Pathogenesis of disorders caused by human P450 oxidoreductase mutations Official URL

Language:

English

Submitter:

Amit Vikram Pandey

Date Deposited:

21 Sep 2016 15:02

Last Modified:

04 Feb 2018 02:05

Publisher DOI:

10.1016/j.jsbmb.2016.03.031

PubMed ID:

27032764

Uncontrolled Keywords:

Adrenal hyperplasia; Antely-Bixler syndrome; CYP19A1; NADPH P450 oxidoreductase; POR; Steroid metabolism

BORIS DOI:

10.7892/boris.88464

URI:

https://boris.unibe.ch/id/eprint/88464

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