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Title: Deletion of P399{sub E}401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency

Abstract

Highlights: {yields} Mutations in human POR cause congenital adrenal hyperplasia. {yields} We are reporting a novel 3 amino acid deletion mutation in POR P399{sub E}401del. {yields} POR mutation P399{sub E}401del decreased P450 activities by 60-85%. {yields} Impairment of steroid metabolism may be caused by multiple hits. {yields} Severity of aromatase inhibition is related to degree of in utero virilization. -- Abstract: P450 oxidoreductase (POR) is the electron donor for all microsomal P450s including steroidogenic enzymes CYP17A1, CYP19A1 and CYP21A2. We found a novel POR mutation P399{sub E}401del in two unrelated Turkish patients with 46,XX disorder of sexual development. Recombinant POR proteins were produced in yeast and tested for their ability to support steroid metabolizing P450 activities. In comparison to wild-type POR, the P399{sub E}401del protein was found to decrease catalytic efficiency of 21-hydroxylation of progesterone by 68%, 17{alpha}-hydroxylation of progesterone by 76%, 17,20-lyase action on 17OH-pregnenolone by 69%, aromatization of androstenedione by 85% and cytochrome c reduction activity by 80%. Protein structure analysis of the three amino acid deletion P399{sub E}401 revealed reduced stability and flexibility of the mutant. In conclusion, P399{sub E}401del is a novel mutation in POR that provides valuable genotype-phenotype and structure-function correlation for mutations in amore » different region of POR compared to previous studies. Characterization of P399{sub E}401del provides further insight into specificity of different P450s for interaction with POR as well as nature of metabolic disruptions caused by more pronounced effect on specific P450s like CYP17A1 and aromatase.« less

Authors:
 [1];  [2];  [1];  [3];  [4];  [3];  [2];  [1]
  1. Pediatric Endocrinology, Diabetology and Metabolism, University Children's Hospital, Bern (Switzerland)
  2. Service d'Endocrinologie Moleculaire et Maladies Rares, Hospices Civils de Lyon, Bron (France)
  3. Hopital Necker-Enfants malades, Paris (France)
  4. Hopital Robert Debre, Paris (France)
Publication Date:
OSTI Identifier:
22207482
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 412; Journal Issue: 4; Other Information: Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AMINO ACIDS; ANDROSTENEDIONE; AROMATIZATION; FIRST AID; GENOTYPE; HYDROXYLATION; HYDROXYPREGNENONE; INHIBITION; METABOLISM; MUTANTS; MUTATIONS; OXIDASES; PATIENTS; PHENOTYPE; PROGESTERONE; PROTEIN STRUCTURE; STRUCTURE FUNCTIONS; YEASTS

Citation Formats

Flueck, Christa E., E-mail: christa.flueck@dkf.unibe.ch, Mallet, Delphine, Hofer, Gaby, Samara-Boustani, Dinane, Leger, Juliane, Polak, Michel, Morel, Yves, and Pandey, Amit V., E-mail: amit@pandeylab.org. Deletion of P399{sub E}401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency. United States: N. p., 2011. Web. doi:10.1016/J.BBRC.2011.08.001.
Flueck, Christa E., E-mail: christa.flueck@dkf.unibe.ch, Mallet, Delphine, Hofer, Gaby, Samara-Boustani, Dinane, Leger, Juliane, Polak, Michel, Morel, Yves, & Pandey, Amit V., E-mail: amit@pandeylab.org. Deletion of P399{sub E}401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency. United States. doi:10.1016/J.BBRC.2011.08.001.
Flueck, Christa E., E-mail: christa.flueck@dkf.unibe.ch, Mallet, Delphine, Hofer, Gaby, Samara-Boustani, Dinane, Leger, Juliane, Polak, Michel, Morel, Yves, and Pandey, Amit V., E-mail: amit@pandeylab.org. Fri . "Deletion of P399{sub E}401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency". United States. doi:10.1016/J.BBRC.2011.08.001.
@article{osti_22207482,
title = {Deletion of P399{sub E}401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency},
author = {Flueck, Christa E., E-mail: christa.flueck@dkf.unibe.ch and Mallet, Delphine and Hofer, Gaby and Samara-Boustani, Dinane and Leger, Juliane and Polak, Michel and Morel, Yves and Pandey, Amit V., E-mail: amit@pandeylab.org},
abstractNote = {Highlights: {yields} Mutations in human POR cause congenital adrenal hyperplasia. {yields} We are reporting a novel 3 amino acid deletion mutation in POR P399{sub E}401del. {yields} POR mutation P399{sub E}401del decreased P450 activities by 60-85%. {yields} Impairment of steroid metabolism may be caused by multiple hits. {yields} Severity of aromatase inhibition is related to degree of in utero virilization. -- Abstract: P450 oxidoreductase (POR) is the electron donor for all microsomal P450s including steroidogenic enzymes CYP17A1, CYP19A1 and CYP21A2. We found a novel POR mutation P399{sub E}401del in two unrelated Turkish patients with 46,XX disorder of sexual development. Recombinant POR proteins were produced in yeast and tested for their ability to support steroid metabolizing P450 activities. In comparison to wild-type POR, the P399{sub E}401del protein was found to decrease catalytic efficiency of 21-hydroxylation of progesterone by 68%, 17{alpha}-hydroxylation of progesterone by 76%, 17,20-lyase action on 17OH-pregnenolone by 69%, aromatization of androstenedione by 85% and cytochrome c reduction activity by 80%. Protein structure analysis of the three amino acid deletion P399{sub E}401 revealed reduced stability and flexibility of the mutant. In conclusion, P399{sub E}401del is a novel mutation in POR that provides valuable genotype-phenotype and structure-function correlation for mutations in a different region of POR compared to previous studies. Characterization of P399{sub E}401del provides further insight into specificity of different P450s for interaction with POR as well as nature of metabolic disruptions caused by more pronounced effect on specific P450s like CYP17A1 and aromatase.},
doi = {10.1016/J.BBRC.2011.08.001},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 412,
place = {United States},
year = {Fri Sep 09 00:00:00 EDT 2011},
month = {Fri Sep 09 00:00:00 EDT 2011}
}