Diminished FAD binding in the Y459H and V492E Antley-Bixler syndrome mutants of human cytochrome P450 reductase.

Diminished FAD binding in the Y459H and V492E Antley-Bixler syndrome mutants of human cytochrome P450 reductase. Research Abstract Details 

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Diminished FAD binding in the Y459H and V492E Antley-Bixler syndrome mutants of human cytochrome P450 reductase. Abstract Text:

Christopher C Marohnic,Satya P Panda,Pavel ,Bettie Sue Masters,

Numerous mutations/polymorphisms of the POR gene, encoding NADPH:cytochrome P450 oxidoreductase (CYPOR), have been described in patients with Antley-Bixler syndrome (ABS), presenting with craniofacial dysmorphogenesis, and/or disordered steroidogenesis, exhibiting ambiguous genitalia. CYPOR is the obligate electron donor to 51 microsomal cytochromes P450 that catalyze critical steroidogenic and xenobiotic reactions, and to two heme oxygenase isoforms, among other redox partners. To address the molecular basis of CYPOR dysfunction in ABS patients, the soluble catalytic domain of human CYPOR was bacterially expressed. WT enzyme was green, due to air-stable FMN semiquinone (blue) and oxidized FAD (yellow). The ABS mutant V492E was blue-gray. Flavin analysis indicated that WT had a protein:FAD:FMN ratio of approximately 1:1:1, whereas approximately 1:0.1:0.9 was observed for V492E, which retained 9% of the WT k(cat)/K(m) in NADPH:cytochrome c reductase assays. V492E was reconstituted upon addition of FAD, post-purification, as shown by flavin analysis, activity assay, and near UV-visible CD. Both Y459H and V492E were expressed as membrane anchor-containing proteins, which also exhibited FAD deficiency. CYP4A4-catalyzed omega-hydroxylation of prostaglandin E1 was supported by WT CYPOR but not by either of the ABS mutants. Hydroxylation activity was rescued for both Y459H and V492E upon addition of FAD to the reaction. Based on these findings, decreased FAD-binding affinity is proposed as the basis of the observed loss of CYPOR function in the Y459H and V492E POR mutations in ABS.

Diminished FAD binding in the Y459H and V492E Antley-Bixler syndrome mutants of human cytochrome P450 reductase. Publishing Authors By Initials

CC Marohnic,SP Panda,P ,BS Masters,

For similar pathological conditions, signs and symptoms: pathologic processes: disease: syndrome research abstracts see: pathological conditions, signs and symptoms: pathologic processes: disease: syndrome research

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Diminished FAD binding in the Y459H and V492E Antley-Bixler syndrome mutants of human cytochrome P450 reductase. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: The Journal of biological chemistry

VOLUME: 281

Page Numbers: 35975-82

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 24

MONTH: 09

YEAR: 2006

Diminished FAD binding in the Y459H and V492E Antley-Bixler syndrome mutants of human cytochrome P450 reductase. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985121

Diminished FAD binding in the Y459H and V492E Antley-Bixler syndrome mutants of human cytochrome P450 reductase. Keywords Mesh Terms:

KEYWORDS: Syndrome

MESH TERMS: physiology

Chemical & Substance for Abstract: Diminished FAD binding in the Y459H and V492E Antley-Bixler syndrome mutants of human cytochrome P450 reductase. Information

Substance Name: NADPH-Ferrihemoprotein Reductase

Registry Number: EC 1.6.2.4

Grant and Affiliation Information for Diminished FAD binding in the Y459H and V492E Antley-Bixler syndrome mutants of human cytochrome P450 reductase.

AFFILIATION: Department of Biochemistry, The University of Texas Health Science Center, San Antonio, Texas 78229, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: HL30050

ACRONYM: HL

MEDLINETA: J Biol Chem

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