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Phenylalanine Residues in the Active Site of CYP2E1 Participate in Determining the Binding Orientation and Metabolism-Dependent Genotoxicity of Aromatic Compounds
Hu, K.; Tu, H.; Xie, J.; Yang, Z.; Li, Z.; Chen, Y.; Liu, Y. Phenylalanine Residues in the Active Site of CYP2E1 Participate in Determining the Binding Orientation and Metabolism-Dependent Genotoxicity of Aromatic Compounds. Toxics2023, 11, 495.
Hu, K.; Tu, H.; Xie, J.; Yang, Z.; Li, Z.; Chen, Y.; Liu, Y. Phenylalanine Residues in the Active Site of CYP2E1 Participate in Determining the Binding Orientation and Metabolism-Dependent Genotoxicity of Aromatic Compounds. Toxics 2023, 11, 495.
Hu, K.; Tu, H.; Xie, J.; Yang, Z.; Li, Z.; Chen, Y.; Liu, Y. Phenylalanine Residues in the Active Site of CYP2E1 Participate in Determining the Binding Orientation and Metabolism-Dependent Genotoxicity of Aromatic Compounds. Toxics2023, 11, 495.
Hu, K.; Tu, H.; Xie, J.; Yang, Z.; Li, Z.; Chen, Y.; Liu, Y. Phenylalanine Residues in the Active Site of CYP2E1 Participate in Determining the Binding Orientation and Metabolism-Dependent Genotoxicity of Aromatic Compounds. Toxics 2023, 11, 495.
Abstract
The amino acid composition of the active site in an enzyme is influential on its substrate selectivity. For CYP2E1, the role of PHE residues in the formation of effective orientations for its activity toward aromatic substrates remains unclear. In this study, molecular docking and molecular dynamics analysis were performed toward the interactions between PHEs in the active site of human CYP2E1 and various aromatic compounds as confirmed CYP2E1 substrates. The results indicated that the orientation of 1-methylpyrene (1-MP) in the active site was highly modulated by the PHEs, PHE478 contributing to the binding free energy most significantly. Furthermore, by building a random forest model the relationship between each of 19 molecular descriptors of PCB congeners (from molecular docking, quantum mechanics, and physicochemical properties) and established human CYP2E1-dependent mutagenicity of a series of polychlorinated biphenyls (PCBs), which have been proven to be human carcinogens and endocrinal disrupters, was investigated. The presence of PHEs did not appear to significantly modify the electronic or structural feature of each bound ligand (PCB), instead, the flexibility of the molecular conformation of PHEs contributed substantially to the effective binding energy and orientation. It is supposed that PHE residues adjust their own conformation to permit a suitable space for the ligand binding and form an orientation favorable for a biochemical reaction. This study has provided some insights into the role of PHEs in guiding the interactive adaptation of the active site of human CYP2E1 for the binding and metabolism of aromatic substrates.
Keywords
aromatic compounds; CYP2E1; phenylalanine; molecular simulation; random forest
Subject
Biology and Life Sciences, Toxicology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
