ArticleBiomolecules2023
Single Mutations in Cytochrome P450 Oxidoreductase Can Alter the Specificity of Human Cytochrome P450 1A2-Mediated Caffeine Metabolism.
Article in Biomolecules, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 11 citations in OpenAlex.
- Deciphering cytochrome P450 reductase role in MASLD: molecular mechanisms and pathophysiological implications.Nature reviews. Gastroenterology & hepatology · 2026Review
- Structural context of NADPH-cytochrome P450 reductase mutations that alter cytochrome P450 1A2 substrate regioselectivity.Drug metabolism and disposition: the biological fate of chemicals · 2026Article
- Dietary Factors Drive Volatile Organic Compound Exposure and Modulate Its Impact on Multi-Dimensional Biological Aging.Food science & nutrition · 2026Article
- A New Fluorogenic Substrate for CYP1A2 and Its Application in Studying the Effects of Alcohol Exposure on Liver Drug Metabolism.bioRxiv : the preprint server for biology · 2026Article
- Mass spectrometry footprinting reveals microsomal CYP2A6 structural changes induced by interaction with its reductase flavin mononucleotide domain.Drug metabolism and disposition: the biological fate of chemicals · 2026Article
- Recent Advances in Elucidating the Mechanism of the NADPH-Cytochrome P450 Reductase-Mediated Electron Transfer Cycle: Experimental and Computational Perspectives.Molecules (Basel, Switzerland) · 2025Review
- Geometry-encoded molecular dynamics enables deep learning insights into P450 regiospecificity control.Scientific reports · 2025Article
- Harnessing Porphyrin Accumulation in Liver Cancer: Combining Genomic Data and Drug Targeting.Biomolecules · 2024Article
- Pharmaceutical removal from wastewater by introducing cytochrome P450s into microalgae.Microbial biotechnology · 2024Review
- Pleiotropy of Progesterone Receptor Membrane Component 1 in Modulation of Cytochrome P450 Activity.Journal of xenobiotics · 2024Review
- Allosteric modulation of cytochrome P450 enzymes by the NADPH cytochrome P450 reductase FMN-containing domain.The Journal of biological chemistry · 2023Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A unique cytochrome P450 (CYP) oxidoreductase (CPR) sustains activities of human microsomal CYPs. Its function requires toggling between a closed conformation enabling electron transfers from NADPH to FAD and then FMN cofactors and open conformations forming complexes and transferring electrons to CYPs. We previously demonstrated that distinct features of the hinge region linking the FAD and FMN domain (FD) modulate conformer poses and their interactions with CYPs. Specific FD residues contribute in a CYP isoform-dependent manner to the recognition and electron transfer mechanisms that are additionally modulated by the structure of CYP-bound substrate. To obtain insights into the underlying mechanisms, we analyzed how hinge region and FD mutations influence CYP1A2-mediated caffeine metabolism. Activities, metabolite profiles, regiospecificity and coupling efficiencies were evaluated in regard to the structural features and molecular dynamics of complexes bearing alternate substrate poses at the CYP active site. Studies reveal that FD variants not only modulate CYP activities but surprisingly the regiospecificity of reactions. Computational approaches evidenced that the considered mutations are generally in close contact with residues at the FD-CYP interface, exhibiting induced fits during complexation and modified dynamics depending on caffeine presence and orientation. It was concluded that dynamic coupling between FD mutations, the complex interface and CYP active site exist consistently with the observed regiospecific alterations.
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