Molecular determinants of xenobiotic metabolism: QM/MM simulation of the conversion of 1-chloro-2,4-dinitrobenzene catalyzed by M1-1 glutathione S-transferase.

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 0370623 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0006-2960 (Print) Linking ISSN: 00062960 NLM ISO Abbreviation: Biochemistry Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, American Chemical Society.
    • Subject Terms:
      Dinitrochlorobenzene/*metabolism ; Glutathione Transferase/*metabolism ; Xenobiotics/*metabolism; Animals ; Catalysis ; Computer Simulation ; Models, Molecular ; Mutation ; Rats
    • Abstract:
      Modeling methods allow the identification and analysis of determinants of reactivity and specificity in enzymes. The reaction between glutathione and 1-chloro-2,4-dinitrobenzene (CDNB) is widely used as a standard activity assay for glutathione S-transferases (GSTs). It is important to understand the causes of differences between catalytic GST isoenzymes and the effects of mutations and genetic polymorphisms. Quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations have been performed here to investigate the addition of the glutathione anion to CDNB in the wild-type M1-1 GST isoenzyme from rat and in three single point mutant (Tyr6Phe, Tyr115Phe, and Met108Ala) M1-1 GST enzymes. We have developed a specifically parameterized QM/MM method (AM1-SRP/CHARMM22) to model this reaction by fitting to experimental heats of formation and ionization potentials. Free energy profiles were obtained from molecular dynamics simulations of the reaction using umbrella sampling and weighted histogram analysis techniques. The reaction in solution has also been simulated and is compared to the enzymatic reaction. The free energies are in excellent agreement with experimental results. Overall the results of the present study show that QM/MM reaction pathway analysis provides detailed insight into the chemistry of GST and can be used to obtain mechanistic insight into the effects of specific mutations on this catalytic process.
    • Accession Number:
      0 (Dinitrochlorobenzene)
      0 (Xenobiotics)
      EC 2.5.1.18 (Glutathione Transferase)
    • Publication Date:
      Date Created: 20070508 Date Completed: 20070706 Latest Revision: 20201209
    • Publication Date:
      20240829
    • Accession Number:
      10.1021/bi0622827
    • Accession Number:
      17480056