ArticleThe Journal of biological chemistry2015
Interactions among cytochromes P450 in microsomal membranes: oligomerization of cytochromes P450 3A4, 3A5, and 2E1 and its functional consequences.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 71 citations in OpenAlex.
- The Role of Cytochrome P450 Holoenzyme Metabolism in the Origin of Neuropathologies.International journal of molecular sciences · 2026Review
- The role of CYP3A-CYP2E1 interactions in activation of CYP3A enzymes by chronic alcohol exposure.bioRxiv : the preprint server for biology · 2026Article
- Functional characterization of CYP1 enzymes: Complex formation, membrane localization and function.Journal of inorganic biochemistry · 2023Article
- The Influence of Lipid Microdomain Heterogeneity on Protein-Protein Interactions: Proteomic Analysis of Co-Immunoprecipitated Binding Partners of P450 1A2 and P450 3A in Rat Liver Microsomes.Drug metabolism and disposition: the biological fate of chemicals · 2023Article
- Fusarium culmorum Produces NX-2 Toxin Simultaneously with Deoxynivalenol and 3-Acetyl-Deoxynivalenol or NivalenolToxins · 2022Article
- Hepatic CYP3A4 Enzyme Compensatively Maintains Endogenous Geranylgeranoic Acid Levels inMetabolites · 2022Article
- Exploring the Interactome of Cytochrome P450 2E1 in Human Liver Microsomes with Chemical Crosslinking Mass Spectrometry.Biomolecules · 2022Article
- Substrates and Loaded Iron Ions Relative Position Influence the Catalytic Characteristics of the MetalloenzymesFrontiers in pharmacology · 2022Article
- Assembling the P450 puzzle: on the sources of nonadditivity in drug metabolism.Trends in pharmacological sciences · 2021Review
- Screening and heterologous expression of flavone synthase and flavonol synthase to catalyze hesperetin to diosmetin.Biotechnology letters · 2021Article
- Probing functional interactions between cytochromes P450 with principal component analysis of substrate saturation profiles and targeted proteomics.Archives of biochemistry and biophysics · 2021Article
- Identification of the contact region responsible for the formation of the homomeric CYP1A2•CYP1A2 complex.The Biochemical journal · 2021Article
- Effects of alcohol-induced increase in CYP2E1 content in human liver microsomes on the activity and cooperativity of CYP3A4.Archives of biochemistry and biophysics · 2021Article
- Heteromeric complex formation between human cytochrome P450 CYP1A1 and heme oxygenase-1.The Biochemical journal · 2021Article
- Numerical Methods for Modeling Enzyme Kinetics.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Domain-Swap Dimerization ofMolecular pharmacology · 2020Article
- Time-dependent enzyme inactivation: Numerical analyses of in vitro data and prediction of drug-drug interactions.Pharmacology & therapeutics · 2020Review
- The Biosynthesis of Enzymatically Oxidized Lipids.Frontiers in endocrinology · 2020Review
- Toward a systems approach to cytochrome P450 ensemble: interactions of CYP2E1 with other P450 species and their impact on CYP1A2.The Biochemical journal · 2019Article
- The Formation of a Camalexin Biosynthetic Metabolon.The Plant cell · 2019Article
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
The body of evidence of physiologically relevant P450-P450 interactions in microsomal membranes continues to grow. Here we probe oligomerization of human CYP3A4, CYP3A5, and CYP2E1 in microsomal membranes. Using a technique based on luminescence resonance energy transfer, we demonstrate that all three proteins are subject to a concentration-dependent equilibrium between the monomeric and oligomeric states. We also observed the formation of mixed oligomers in CYP3A4/CYP3A5, CYP3A4/CYP2E1, and CYP3A5/CYP2E1 pairs and demonstrated that the association of either CYP3A4 or CYP3A5 with CYP2E1 causes activation of the latter enzyme. Earlier we hypothesized that the intersubunit interface in CYP3A4 oligomers is similar to that observed in the crystallographic dimers of some microsomal drug-metabolizing cytochromes P450 (Davydov, D. R., Davydova, N. Y., Sineva, E. V., Kufareva, I., and Halpert, J. R. (2013) Pivotal role of P450-P450 interactions in CYP3A4 allostery: the case of α-naphthoflavone. Biochem. J. 453, 219-230). Here we report the results of intermolecular cross-linking of CYP3A4 oligomers with thiol-reactive bifunctional reagents as well as the luminescence resonance energy transfer measurements of interprobe distances in the oligomers of labeled CYP3A4 single-cysteine mutants. The results provide compelling support for the physiological relevance of the dimer-specific peripheral ligand-binding site observed in certain CYP3A4 structures. According to our interpretation, these results reveal an important general mechanism that regulates the activity and substrate specificity of the cytochrome P450 ensemble through interactions between multiple P450 species. As a result of P450-P450 cross-talk, the catalytic properties of the cytochrome P450 ensemble cannot be predicted by simple summation of the properties of the individual P450 species.
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