5a1r › Citations

Anion-Dependent Stimulation of CYP3A4 Monooxygenase.

Sevrioukova IF, Poulos TL
Biochemistry 54 4083-96 (2015)
Cited: 28 times
EuropePMC logo PMID: 26066995

Abstract

We co-crystallized human cytochrome P450 3A4 (CYP3A4) with progesterone (PRG) under two different conditions, but the resulting complexes contained only one PRG molecule bound to the previously identified peripheral site. A novel feature in one of our structures is a citrate ion, originating from the crystallization solution. The citrate-binding site is located in an area where the N-terminus splits from the protein core and, thus, is suitable for the interaction with the anionic phospholipids of the microsomal membrane. We investigated how citrate affects the function of a soluble CYP3A4 monooxygenase system consisting of equimolar amounts of CYP3A4 and cytochrome P450 reductase (CPR). Citrate was found to affect the properties of both redox partners and stimulated their catalytic activities in a concentration-dependent manner via a complex mechanism. CYP3A4-substrate binding, reduction of CPR with NADPH, and interflavin and interprotein electron transfer were identified as citrate-sensitive steps. Comparative analysis of various negatively charged organic compounds indicated that, in addition to alterations caused by changes in ionic strength, anions modulate the properties of CYP3A4 and CPR through specific anion-protein interactions. Our results help to better understand previous observations and provide new mechanistic insights into CYP3A4 function.

Articles - 5a1r mentioned but not cited (5)

  1. Midazolam as a Probe for Drug-Drug Interactions Mediated by CYP3A4: Homotropic Allosteric Mechanism of Site-Specific Hydroxylation. Denisov IG, Grinkova YV, Camp T, McLean MA, Sligar SG. Biochemistry 60 1670-1681 (2021)
  2. Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4: Insight from Computational Studies. Li J, Chen Y, Tang Y, Li W, Tu Y. J Chem Inf Model 61 2418-2426 (2021)
  3. Functional impact of cytochrome P450 3A (CYP3A) missense variants in cattle. Giantin M, Rahnasto-Rilla M, Tolosi R, Lucatello L, Pauletto M, Guerra G, Pezzato F, Lopparelli RM, Merlanti R, Carnier P, Capolongo F, Honkakoski P, Dacasto M. Sci Rep 9 19672 (2019)
  4. Geodemographic Patterns of Meat Expenditure in Great Britain. James WHM, Lomax N, Birkin M, Collins LM. Appl Spat Anal Policy 14 563-590 (2021)
  5. Transgenic Expression of Haemonchus contortus Cytochrome P450 Hco-cyp-13A11 Decreases Susceptibility to Particular but Not All Macrocyclic Lactones in the Model Organism Caenorhabditis elegans. Jakobs N, Yilmaz E, Krücken J. Int J Mol Sci 23 9155 (2022)


Reviews citing this publication (3)

  1. Recent Structural Insights into Cytochrome P450 Function. Guengerich FP, Waterman MR, Egli M. Trends Pharmacol Sci 37 625-640 (2016)
  2. Cytochrome P450 Organization and Function Are Modulated by Endoplasmic Reticulum Phospholipid Heterogeneity. Brignac-Huber LM, Park JW, Reed JR, Backes WL. Drug Metab Dispos 44 1859-1866 (2016)
  3. CYP2J2 Molecular Recognition: A New Axis for Therapeutic Design. Das A, Weigle AT, Arnold WR, Kim JS, Carnevale LN, Huff HC. Pharmacol Ther 215 107601 (2020)

Articles citing this publication (20)

  1. Structural basis for regiospecific midazolam oxidation by human cytochrome P450 3A4. Sevrioukova IF, Poulos TL. Proc Natl Acad Sci U S A 114 486-491 (2017)
  2. High-Level Production and Properties of the Cysteine-Depleted Cytochrome P450 3A4. Sevrioukova IF. Biochemistry 56 3058-3067 (2017)
  3. Membrane-embedded substrate recognition by cytochrome P450 3A4. Hackett JC. J Biol Chem 293 4037-4046 (2018)
  4. Conformational Mobility in Cytochrome P450 3A4 Explored by Pressure-Perturbation EPR Spectroscopy. Davydov DR, Yang Z, Davydova N, Halpert JR, Hubbell WL. Biophys J 110 1485-1498 (2016)
  5. The use of isomeric testosterone dimers to explore allosteric effects in substrate binding to cytochrome P450 CYP3A4. Denisov IG, Mak PJ, Grinkova YV, Bastien D, Bérubé G, Sligar SG, Kincaid JR. J Inorg Biochem 158 77-85 (2016)
  6. Inhibition of Human CYP3A4 by Rationally Designed Ritonavir-Like Compounds: Impact and Interplay of the Side Group Functionalities. Samuels ER, Sevrioukova I. Mol Pharm 15 279-288 (2018)
  7. Interaction of Human Drug-Metabolizing CYP3A4 with Small Inhibitory Molecules. Sevrioukova I. Biochemistry 58 930-939 (2019)
  8. Structure-Activity Relationships of Rationally Designed Ritonavir Analogues: Impact of Side-Group Stereochemistry, Headgroup Spacing, and Backbone Composition on the Interaction with CYP3A4. Samuels ER, Sevrioukova I. Biochemistry 58 2077-2087 (2019)
  9. Structural Perspectives of the CYP3A Family and Their Small Molecule Modulators in Drug Metabolism. Wright WC, Chenge J, Chen T. Liver Res 3 132-142 (2019)
  10. 7,8-benzoflavone binding to human cytochrome P450 3A4 reveals complex fluorescence quenching, suggesting binding at multiple protein sites. Marsch GA, Carlson BT, Guengerich FP. J Biomol Struct Dyn 36 841-860 (2018)
  11. Conformational Response of N-Terminally Truncated Cytochrome P450 3A4 to Ligand Binding in Solution. Chuo SW, Liou SH, Wang LP, Britt RD, Poulos TL, Sevrioukova IF, Goodin DB. Biochemistry 58 3903-3910 (2019)
  12. Conformational selection is present in ligand binding to cytochrome P450 19A1 lipoprotein nanodiscs. Zárate-Pérez F, Hackett JC. J Inorg Biochem 209 111120 (2020)
  13. Midazolam as a Probe for Heterotropic Drug-Drug Interactions Mediated by CYP3A4. Denisov IG, Grinkova YV, McLean MA, Camp T, Sligar SG. Biomolecules 12 853 (2022)
  14. Structural Dynamics of Cytochrome P450 3A4 in the Presence of Substrates and Cytochrome P450 Reductase. Ducharme J, Sevrioukova IF, Thibodeaux CJ, Auclair K. Biochemistry 60 2259-2271 (2021)
  15. Steroid bioconjugation to a CYP3A4 allosteric site and its effect on substrate binding and coupling efficiency. Polic V, Sevrioukova IF, Auclair K. Arch Biochem Biophys 653 90-96 (2018)
  16. Structure of Yak Lactoperoxidase at 1.55 Å Resolution. Viswanathan V, Rani C, Ahmad N, Singh PK, Sharma P, Kaur P, Sharma S, Singh TP. Protein J 40 8-18 (2021)
  17. The Cytochrome P450 3A4 has three Major Conformations: New Clues to Drug Recognition by this Promiscuous Enzyme. Benkaidali L, André F, Moroy G, Tangour B, Maurel F, Petitjean M. Mol Inform 36 (2017)
  18. In vitro evaluation of the metabolic enzymes and drug interaction potential of triapine. Joshi A, Kiesel BF, Chaphekar N, Jones R, Guo J, Kunos CA, Taylor S, Chu E, Venkataramanan R, Beumer JH. Cancer Chemother Pharmacol 86 633-640 (2020)
  19. Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment. Samuels ER, Sevrioukova IF. Int J Mol Sci 23 7291 (2022)
  20. Interaction of CYP3A4 with caffeine: First insights into multiple substrate binding. Sevrioukova IF. J Biol Chem 299 105117 (2023)


Quick links