Metabolic activation mechanism of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB136) by cytochrome P450 2B6: A QM/MM approach.

Cytochrome P450 enzymes (CYPs) play an essential role in the bio-transformation of polychlorinated biphenyls (PCBs). The present work implemented quantum mechanic/molecular mechanic methods (QM/MM) and density functional theory (DFT) to study the metabolic activation of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB136) catalyzed by CYP2B6. Electrophilic additions at the Cα and Cβ positions generate different active intermediates. The electrophilic addition energy barrier of Cβ is 10.9 kcal/mol higher than that of Cα, and Cα is the preferred site for the electrophilic addition reaction. Based on the previous experimental studies, this work investigated the mechanism of converting active intermediates into OH-PCB136, which has high toxicity in a non-enzymatic environment. Structural analysis via the electrostatic and noncovalent interactions indicates that Phe108, Ile114, Phe115, Phe206, Phe297, Ala298, Leu363, Val367, TIP32475 and TIP32667 play crucial roles in substrate recognition and metabolism. The analysis suggests that the halogen-π interactions are important factors for the metabolism of CYP2B6 to halogenated environmental pollutants. This work improved the understanding of the metabolism and activation process of chiral PCBs, and can be used as a guide to improve the microbial degradation efficiency of PCB136.

• Publication year

  2021

• Venue

  Science of the Total Environment

• Publication date

  2021-02-04

• Fields of study

  Medicine, Chemistry, Environmental Science

• Identifiers
  DOI 10.1016/j.scitotenv.2021.145579PMID 33652317
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Synergy between Experiments and Computations: A Green Channel for Revealing Metabolic Mechanism of Xenobiotics in Chemical Toxicology.

  2020cited by this paper
• Degradation mechanism of biphenyl and 4-4'-dichlorobiphenyl cis-dihydroxylation by non-heme 2,3 dioxygenases BphA: A QM/MM approach.

  2020cited by this paper
• Determination and Environmental Implications of Aqueous-Phase Rate Constants in Radical Reactions.

  2020cited by this paper
• Computational study on the metabolic activation mechanism of PeCDD by Cytochrome P450 1A1.

  2020cited by this paper
• A proposed method of enantioselectivity analysis for residual chiral PCBs in gas chromatography.

  2019cited by this paper
• Xenobiotic Metabolism by Cytochrome P450 Enzymes: Insights Gained from Molecular Simulations

  2019cited by this paper
• Historical record of polychlorinated biphenyls (PCBs) in the continental shelf of the Korea Strait.

  2019cited by this paper
• Atropselective Disposition of 2,2',3,4',6-Pentachlorobiphenyl (PCB 91) and Identification of Its Metabolites in Mice with Liver-specific Deletion of Cytochrome P450 Reductase.

  2019cited by this paper
• Degradation mechanism for Zearalenone ring-cleavage by Zearalenone hydrolase RmZHD: A QM/MM study.

  2019cited by this paper
• Toxicokinetics of Chiral PCB 136 and Its Hydroxylated Metabolites in Mice with a Liver-Specific Deletion of Cytochrome P450 Reductase.

  2019cited by this paper
• Climatic Influence on Temporal Trends of Polychlorinated Biphenyls and Organochlorine Pesticides in Landlocked Char from Lakes in the Canadian High Arctic.

  2018cited by this paper
• TTClust: A Versatile Molecular Simulation Trajectory Clustering Program with Graphical Summaries

  2018cited by this paper
• ROLE OF CYTOCHROME P450S IN THE GENERATION AND METABOLISM OF REACTIVE OXYGEN SPECIES.

  2018cited by this paper
• Atropisomers of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) exhibit stereoselective effects on activation of nuclear receptors in vitro

  2018cited by this paper
• Hydroxyl Radical Based Photocatalytic Degradation of Halogenated Organic Contaminants and Paraffin on Silica Gel.

  2018cited by this paper
• Halogen-π Interactions in the Cytochrome P450 Active Site: Structural Insights into Human CYP2B6 Substrate Selectivity.

  2017cited by this paper
• PCB 28 metabolites elimination kinetics in human plasma on a real case scenario: Study of hydroxylated polychlorinated biphenyl (OH-PCB) metabolites of PCB 28 in a highly exposed German Cohort.

  2017cited by this paper
• Distribution and depth profiles of polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and polychlorinated biphenyls in sediment collected from offshore waters of Central Vietnam.

  2016cited by this paper
• Chiral polychlorinated biphenyls: absorption, metabolism and excretion—a review

  2016cited by this paper
• Over 100-year sedimentary record of polycyclic aromatic hydrocarbons (PAHs) and organochlorine compounds (OCs) in the continental shelf of the East China Sea.

  2016cited by this paper
• Detoxification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes: A theoretical investigation.

  2016cited by this paper
• Effects of thiol antioxidants on the atropselective oxidation of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) by rat liver microsomes

  2016cited by this paper
• Oxidative degradation of decabromodiphenyl ether (BDE 209) by potassium permanganate: reaction pathways, kinetics, and mechanisms assisted by density functional theory calculations.

  2015cited by this paper
• Ozonation of indigo enhanced by carboxylated carbon nanotubes: performance optimization, degradation products, reaction mechanism and toxicity evaluation.

  2015cited by this paper
• Prediction of cytochrome P450 mediated metabolism.

  2015cited by this paper
• Metabolism and metabolites of polychlorinated biphenyls

  2015cited by this paper
• Dioxins and PCBs in feed and food--review from European perspective.

  2014cited by this paper
• ChemShell—a modular software package for QM/MM simulations

  2014cited by this paper
• Hepatic Metabolism Affects the Atropselective Disposition of 2,2′,3,3′,6,6′-Hexachlorobiphenyl (PCB 136) in Mice

  2014cited by this paper
• Wavefunction and reactivity study of benzo[a]pyrene diol epoxide and its enantiomeric forms

  2014cited by this paper
• Metabolism of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) atropisomers in tissue slices from phenobarbital or dexamethasone-induced rats is sex-dependent

  2013cited by this paper
• Stereoselective formation of mono- and dihydroxylated polychlorinated biphenyls by rat cytochrome P450 2B1.

  2013cited by this paper
• Effects of Dispersion in Density Functional Based Quantum Mechanical/Molecular Mechanical Calculations on Cytochrome P450 Catalyzed Reactions.

  2012cited by this paper
• Multiwfn: A multifunctional wavefunction analyzer

  2012cited by this paper
• Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling.

  2012cited by this paper
• Polychlorinated biphenyls and their hydroxylated metabolites in placenta from Madrid mothers

  2011cited by this paper
• 2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) is enantioselectively oxidized to hydroxylated metabolites by rat liver microsomes.

  2011cited by this paper
• SwissParam: A fast force field generation tool for small organic molecules

  2011cited by this paper
• Revealing noncovalent interactions.

  2010cited by this paper
• Assessment of the disposition of chiral polychlorinated biphenyls in female mdr 1a/b knockout versus wild-type mice using multivariate analyses.

  2010cited by this paper
• Exposure to Hydroxylated Polychlorinated Biphenyls (OH-PCBs) in the Prenatal Period and Subsequent Neurodevelopment in Eastern Slovakia

  2009cited by this paper
• AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading

  2009cited by this paper
• QM/MM modeling of benzene hydroxylation in human cytochrome P450 2C9.

  2008cited by this paper
• 2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) atropisomers interact enantioselectively with hepatic microsomal cytochrome P450 enzymes.

  2008cited by this paper
• A study on PCB, PCDD/PCDF industrial contamination in a mixed urban-agricultural area significantly affecting the food chain and the human exposure. Part I: soil and feed.

  2007cited by this paper
• Biotransformation of polychlorinated biphenyls (PCBs) and bioformation of hydroxylated PCBs in fish.

  2006cited by this paper
• Structure-activity relationship for noncoplanar polychlorinated biphenyl congeners toward the ryanodine receptor-Ca2+ channel complex type 1 (RyR1).

  2006cited by this paper
• PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations

  2004cited by this paper
• Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes.

  2004cited by this paper
• Fetal Exposure to PCBs and Their Hydroxylated Metabolites in a Dutch Cohort

  2004cited by this paper
• What factors affect the regioselectivity of oxidation by cytochrome p450? A DFT study of allylic hydroxylation and double bond epoxidation in a model reaction.

  2002cited by this paper
• The elusive oxidant species of cytochrome P450 enzymes: characterization by combined quantum mechanical/molecular mechanical (QM/MM) calculations.

  2002cited by this paper
• 2,2',3,3',6,6'-hexachlorobiphenyl hydroxylation by active site mutants of cytochrome P450 2B1 and 2B11.

  1999cited by this paper
• VMD: visual molecular dynamics.

  1996cited by this paper
• DL_POLY_2.0: a general-purpose parallel molecular dynamics simulation package.

  1996cited by this paper
• Average local ionization energies on the molecular surfaces of aromatic systems as guides to chemical reactivity

  1990cited by this paper
• ELECTRONIC STRUCTURE CALCULATIONS ON WORKSTATION COMPUTERS: THE PROGRAM SYSTEM TURBOMOLE

  1989cited by this paper
• Comparison of simple potential functions for simulating liquid water

  1983cited by this paper

• Impact of electrostatic distribution in CYP3A4 on the regioselectivity of triazolam metabolism and regulation of its metabolic rate by the iron spin states: Insights from MD simulations and QM calculations.

  2025cites this paper
• Recent Advances in P450 Enzyme Engineering for the Production of Natural Products

  2025cites this paper
• Metabolism Exploration of Disinfection Byproducts Halonitromethanes (HNMs) by Cytochrome P450 Enzymes and Toxicity Evaluation.

  2025cites this paper
• Novel role of Silver(I) as electron shuttle for polymerization of chlorophenols by permanganate oxidation.

  2025cites this paper
• Integrated transcriptomics and metabolomics analyses reveal the aerobic biodegradation and molecular mechanisms of 2,3',4,4',5-pentachlorodiphenyl (PCB 118) in Methylorubrum sp. ZY-1.

  2024cites this paper
• Mechanism of 7H-Dibenzo[c,g]carbazole metabolism in cytochrome P450 1A1: Insights from computational studies.

  2024cites this paper
• New insight into molecular mechanism of P450-Catalyzed metabolism of emerging contaminants and its consequence for human health: A case study of preservative methylparaben.

  2023cites this paper
• Ant nest-like hierarchical porous imprinted resin-dispersive solid-phase extraction for selective extraction and determination of polychlorinated biphenyls in milk.

  2022cites this paper
• Contributions of Beneficial Microorganisms in Soil Remediation and Quality Improvement of Medicinal Plants

  2022cites this paper
• Computational Study of the Peroxygenase Mechanism Catalyzed by Hemoglobin Dehaloperoxidase Involved in the Degradation of Chlorophenols.

  2022cites this paper
• Computational biotransformation of polyethylene terephthalate by depolymerase: A QM/MM approach.

  2021cites this paper
• Theoretical sight into hydrogen bond interactions between arsenious acid and thiols in aqueous and HEPES solutions

  2021cites this paper
• IsPETase- and IsMHETase-Catalyzed Cascade Degradation Mechanism toward Polyethylene Terephthalate

  2021cites this paper