Electron transfer by human wild-type and A287P mutant P450 oxidoreductase assessed by transient kinetics: functional basis of P450 oxidoreductase deficiency

The Biochemical Journal
Yi JinWalter L Miller

Abstract

Cytochrome P450 oxidoreductase (POR) is a 2-flavin protein that transfers electrons from NADPH via its FAD and FMN moieties to all microsomal cytochrome P450 enzymes, including steroidogenic and drug-metabolizing P450s. Defects in the POR gene can cause POR deficiency (PORD), manifested clinically by disordered steroidogenesis, genital anomalies and skeletal malformations. We examined the POR mutant A287P, which is the most frequent cause of PORD in patients of European ancestry and partially disrupts most P450 activities in vitro. Flavin content analysis showed that A287P is deficient in FAD and FMN binding, although the mutation site is distant from the binding sites of both flavins. Externally added flavin partially restored the cytochrome c reductase activity of A287P, suggesting that flavin therapy may be useful for this frequent form of PORD. Transient kinetic dissection of the reaction of POR with NADPH and the reduction in cytochrome c by POR using stopped-flow techniques revealed defects in individual electron transfer steps mediated by A287P. A287P had impaired ability to accept electrons from NADPH, but was capable of a fast FMN → cytochrome c electron donation reaction. Thus the reduced rates of P450 activities with...Continue Reading

References

Aug 5, 1997·Proceedings of the National Academy of Sciences of the United States of America·M WangJ J Kim
Feb 20, 1999·The Journal of Biological Chemistry·A L ShenC B Kasper
May 24, 2001·The Journal of Biological Chemistry·P A HubbardJ J Kim
Aug 18, 2006·Current Opinion in Pediatrics·Christa E Flück, Walter L Miller
Sep 26, 2006·The Journal of Biological Chemistry·Christopher C MarohnicBettie Sue Masters
Jun 28, 2007·Molecular Endocrinology·Amit V PandeyChrista E Flück
Jan 31, 2008·Proceedings of the National Academy of Sciences of the United States of America·Ningwu HuangWalter L Miller
Jun 14, 2008·Pharmacogenetics and Genomics·Vishal AgrawalWalter L Miller
Oct 22, 2008·Molecular and Cellular Endocrinology·Walter L MillerKathleen M Giacomini
Oct 20, 2009·The Journal of Clinical Endocrinology and Metabolism·Taninee SahakitrungruangWalter L Miller
Oct 28, 2009·The Journal of Biological Chemistry·Jacqueline EllisGordon C K Roberts
Nov 4, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Christopher C MarohnicMichel Kranendonk
Mar 2, 2010·Molecular and Cellular Endocrinology·Catherine NicoloAmit V Pandey
Aug 11, 2010·Pharmacogenetics and Genomics·Vishal AgrawalWalter L Miller
Sep 17, 2010·European Journal of Endocrinology·Dorota Tomalik-ScharteWiebke Arlt
Oct 14, 2010·Pharmacogenetics and Genomics·Duanpen SandeeWalter L Miller
Nov 13, 2010·Molecular and Cellular Endocrinology·Walter L MillerKathleen M Giacomini
Feb 25, 2011·The Journal of Biological Chemistry·Chuanwu XiaJung-Ja P Kim
Jul 12, 2011·Archives of Biochemistry and Biophysics·Christopher C MarohnicBettie Sue S Masters
Aug 3, 2011·Proceedings of the National Academy of Sciences of the United States of America·Chuanwu XiaJung-Ja P Kim
Dec 14, 2011·The Journal of Clinical Endocrinology and Metabolism·Nils KroneWiebke Arlt
Jan 9, 2013·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Daniel W NebertWalter L Miller
Jan 29, 2013·Pharmacology & Therapeutics·Amit V Pandey, Christa E Flück

❮ Previous
Next ❯

Citations

Oct 31, 2016·Genomics, Proteomics & Bioinformatics·Shabbir AhmedShu-Qing Chen
Jul 1, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Yuki HoriTetsuya Aiba
Apr 23, 2019·Plant Disease·Gustavo A Díaz-CruzBryan J Cassone

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.