POR Human, Active
Description
Functional Role in Drug Metabolism
POR serves as the sole electron donor for all microsomal cytochrome P450 enzymes, facilitating oxidative reactions critical for drug metabolism . Key findings include:
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Metronidazole Activation: POR reduces metronidazole in anaerobic bacteria and parasites, generating cytotoxic radicals that disrupt DNA and proteins .
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Human-Specific Metabolism Models: Humanized PIRF mice (murine Por-deficient) reconstituted with human hepatocytes show enhanced production of human-specific drug metabolites (e.g., gefitinib’s M4 and M28 metabolites) compared to conventional models .
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Steroidogenesis: POR mutations disrupt steroid hormone synthesis, leading to disorders like cytochrome P450 oxidoreductase deficiency (PORD), characterized by skeletal and reproductive abnormalities .
Preclinical Drug Development
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Humanized Mouse Models: Deletion of murine Por in PIRF mice results in >95% human hepatocyte repopulation. These models produce human metabolites at higher concentrations (e.g., 3-fold increase in gefitinib’s M4 metabolite) .
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Enzyme Activity Assays: Recombinant POR is used to study interactions with cytochrome P450 isoforms, such as CYP3A4 and CYP2D6, under controlled conditions .
Genetic Variants and Disease
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Over 50 POR mutations are linked to PORD, including amino acid substitutions (e.g., p.A287P) that reduce enzymatic activity by 60–80% .
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A global database (LOVD) catalogs 284 POR variants, 136 of which are unique pathogenic mutations affecting steroidogenesis .
Clinical and Regulatory Considerations
Product Specs
The purity of the product is determined by SDS-PAGE analysis and is greater than 95.0%.
| The specific activity of the enzyme is determined to be greater than 4,000 pmol/min/mg. This value is established by measuring the enzyme's ability to reduce 1 picomole of cytochrome-C per minute per milligram of enzyme using NADPH as the electron donor. The assay is conducted at a pH of 8 and a temperature of 25°C. |
Product Science Overview
P450 Oxidoreductase (POR), also known as NADPH:ferrihemoprotein oxidoreductase, is a crucial enzyme in the electron transfer chain. It facilitates the transfer of electrons from NADPH to cytochrome P450 and other heme proteins, including heme oxygenase, within the endoplasmic reticulum of eukaryotic cells .
The human POR gene is located on chromosome 7 (7q11.23) and comprises 16 exons. The exons 2-16 encode a 677-amino acid POR protein . The POR protein is a membrane-bound enzyme composed of four structural domains: the FMN-binding domain, the connecting domain, the FAD-binding domain, and the NADPH-binding domain. The FMN-binding domain is similar to the structure of FMN-containing protein flavodoxin, while the FAD-binding and NADPH-binding domains resemble those of flavoprotein ferredoxin-NADP+ reductase (FNR) .
POR plays a vital role in the electron transfer process, which is essential for the catalytic activity of all microsomal cytochrome P450 enzymes. These enzymes are involved in the biosynthesis of cholesterol, sterols, and steroid hormones, as well as the metabolism of more than 80% of clinically used drugs . The general electron flow in the POR/P450 system is: NADPH → FAD → FMN → P450 → O2 .
Recombinant human POR can be expressed in E. coli and purified for various experimental purposes. This process involves genotyping human POR for common polymorphisms, expression in E. coli, and purification of the recombinant protein . The activity of wild-type and mutant POR proteins can be assessed to understand their effects on the activity of various cytochromes P450 .
Human POR deficiency can lead to a complex disorder of steroidogenesis and, in severe cases, a skeletal disorder known as Antley-Bixler syndrome . The POR gene is highly polymorphic, with numerous single-nucleotide polymorphisms (SNPs) identified in different ethnic groups. These polymorphisms can affect drug metabolism and steroid biosynthesis, contributing to pharmacogenetic variation in drug response and variations in steroid synthesis .
