ArticleBiochemistry2011
Allosteric activation of cytochrome P450 3A4 by α-naphthoflavone: branch point regulation revealed by isotope dilution analysis.
Article in Biochemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 42 citations in OpenAlex.
- Comprehensive In Vitro Metabolic Characterization of Eudesmin in Human and Mouse Hepatocytes.Pharmaceutics · 2026Article
- Nanodisc-embedded cytochrome P450 P3A4 binds diverse ligands by distributing conformational dynamics to its flexible elements.Journal of inorganic biochemistry · 2023Article
- Low molecular weight ligands bind to CYP3A4 via a branched induced fit mechanism: Implications for OArchives of biochemistry and biophysics · 2023Article
- Article
- Mechanisms of allosteric and mixed mode aromatase inhibitors.RSC chemical biology · 2021Article
- Meloxicam methyl group determines enzyme specificity for thiazole bioactivation compared to sudoxicam.Toxicology letters · 2021Article
- Conformational selection is present in ligand binding to cytochrome P450 19A1 lipoprotein nanodiscs.Journal of inorganic biochemistry · 2020Article
- Dynamics and Location of the Allosteric Midazolam Site in Cytochrome P4503A4 in Lipid Nanodiscs.Biochemistry · 2020Article
- Steroid bioconjugation to a CYP3A4 allosteric site and its effect on substrate binding and coupling efficiency.Archives of biochemistry and biophysics · 2018Article
- CW EPR parameters reveal cytochrome P450 ligand binding modes.Journal of inorganic biochemistry · 2018Article
- CYP26C1 Is a Hydroxylase of Multiple Active Retinoids and Interacts with Cellular Retinoic Acid Binding Proteins.Molecular pharmacology · 2018Article
- Membrane-embedded substrate recognition by cytochrome P450 3A4.The Journal of biological chemistry · 2018Article
- 7,8-benzoflavone binding to human cytochrome P450 3A4 reveals complex fluorescence quenching, suggesting binding at multiple protein sites.Journal of biomolecular structure & dynamics · 2018Article
- Direct protein-protein interactions and substrate channeling between cellular retinoic acid binding proteins and CYP26B1.FEBS letters · 2016Article
- Membrane Interactions, Ligand-Dependent Dynamics, and Stability of Cytochrome P4503A4 in Lipid Nanodiscs.Biochemistry · 2016Article
- Mechanism of drug-drug interactions mediated by human cytochrome P450 CYP3A4 monomer.Biochemistry · 2015Article
- Drug modulation of water-heme interactions in low-spin P450 complexes of CYP2C9d and CYP125A1.Biochemistry · 2015Article
- Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions.Advances in experimental medicine and biology · 2015Review
- Strength of axial water ligation in substrate-free cytochrome P450s is isoform dependent.Biochemistry · 2014Article
- Cytochrome P450-dependent catabolism of vitamin K: ω-hydroxylation catalyzed by human CYP4F2 and CYP4F11.Biochemistry · 2013Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Cytochrome P450 3A4 (CYP3A4) is the dominant xenobiotic metabolizing CYP. Despite great interest in CYP enzymology, two in vitro aspects of CYP3A4 catalysis are still not well understood, namely, sequential metabolism and allosteric activation. We have therefore investigated such a system in which both phenomena are present. Here we report that the sequential metabolism of Nile Red (NR) is accelerated by the heterotropic allosteric effector α-naphthoflavone (ANF). ANF increases the rates of formation for NR metabolites M1 and M2 and also perturbs the metabolite ratio in favor of M2. Thus, ANF has as an allosteric effect on a kinetic branch point. Co-incubating deuterium-labeled NR and unlabeled M1, we show that ANF increases k(cat)/k(off) ~1.8-fold in favor of the k(cat) of M2 production. Steady-state metabolic experiments are analyzed using a kinetic model in which the enzyme and substrates are not in rapid equilibrium, and this distinction allows for the estimation of rates of catalysis for the formation of both the primary (M1) and secondary (M2) products, as well as the partitioning of enzyme between these states. These results are compared with those of earlier spectroscopic investigations of NR and ANF cooperativity, and a mechanism of ANF heteroactivation is presented that involves effects on substrate off rate and coupling efficiency.
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