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Replication of the Enzymatic Temperature Dependency of the Primary Hydride Kinetic Isotope Effects in Solution: Caused by the Protein-Controlled Rigidity of the Donor–Acceptor Centers?

  • Yun Lu*
    Yun Lu
    Department of Chemistry, Southern Illinois University Edwardsville, Edwardsville, Illinois 62026, United States
    *E-mail: [email protected]
    More by Yun Lu
  • Samantha Wilhelm
    Samantha Wilhelm
    Department of Chemistry, Southern Illinois University Edwardsville, Edwardsville, Illinois 62026, United States
  • Mingxuan Bai
    Mingxuan Bai
    Department of Chemistry, Southern Illinois University Edwardsville, Edwardsville, Illinois 62026, United States
    More by Mingxuan Bai
  • Peter Maness
    Peter Maness
    Department of Chemistry, Southern Illinois University Edwardsville, Edwardsville, Illinois 62026, United States
    More by Peter Maness
  • , and 
  • Li Ma
    Li Ma
    Department of Chemistry, Southern Illinois University Edwardsville, Edwardsville, Illinois 62026, United States
    More by Li Ma
Cite this: Biochemistry 2019, 58, 39, 4035–4046
Publication Date (Web):September 3, 2019
https://doi.org/10.1021/acs.biochem.9b00574
Copyright © 2019 American Chemical Society
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Abstract

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The change from the temperature independence of the primary (1°) H/D kinetic isotope effects (KIEs) in wild-type enzyme-catalyzed H-transfer reactions (ΔEa = EaDEaH ∼ 0) to a strong temperature dependence with the mutated enzymes (ΔEa ≫ 0) has recently been frequently observed. This has prompted some enzymologists to develop new H-tunneling models to correlate ΔEa with the donor–acceptor distance (DAD) at the tunneling-ready state (TRS) as well as the protein thermal motions/dynamics that sample the short DADTRS’s for H-tunneling to occur. While extensive evidence supporting or disproving the thermally activated DAD sampling concept has emerged, a comparable study of the simpler bimolecular H-tunneling reactions in solution has not been carried out. In particular, small ΔEa’s (∼0) have not been found. In this paper, we report a study of the hydride-transfer reactions from four NADH models to the same hydride acceptor in acetonitrile. The ΔEa’s were determined: 0.37 (small), 0.60, 0.99, and 1.53 kcal/mol (large). The α-secondary (2°) KIEs on the acceptor that serve as a ruler for the rigidity of reaction centers were previously reported or determined. All possible productive reactant complex (PRC) configurations were computed to provide insight into the structures of the TRS’s. Relationships among structures, 2° KIEs, DADPRC’s, and ΔEa’s were discussed. The more rigid system with more suppressed 2° C–H vibrations at the TRS and more narrowly distributed DADPRC’s in PRCs gave a smaller ΔEa. The results replicated the trend observed in enzymes versus mutated enzymes and appeared to support the concepts of different thermally activated DADTRS sampling processes in response to the rigid versus flexible donor–acceptor centers.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.biochem.9b00574.

  • Detailed kinetic data, CT absorption bands, atomic coordinates and total energies of the structures, calculation of the gas-phase ΔG°’s, synthesis of TMBIH and its deuterated analogue, and 1H NMR spectra (PDF)

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Cited By


This article is cited by 3 publications.

  1. Christian Rapp, Bernd Nidetzky. Hydride Transfer Mechanism of Enzymatic Sugar Nucleotide C2 Epimerization Probed with a Loose-Fit CDP-Glucose Substrate. ACS Catalysis 2022, 12 (12) , 6816-6830. https://doi.org/10.1021/acscatal.2c00257
  2. Mingxuan Bai, Shailendra Koirala, Yun Lu. Direct Correlation between Donor–Acceptor Distance and Temperature Dependence of Kinetic Isotope Effects in Hydride-Tunneling Reactions of NADH/NAD+ Analogues. The Journal of Organic Chemistry 2021, 86 (11) , 7500-7507. https://doi.org/10.1021/acs.joc.1c00497
  3. Peter Maness, Shailendra Koirala, Pratichhya Adhikari, Nasim Salimraftar, Yun Lu. Substituent Effects on Temperature Dependence of Kinetic Isotope Effects in Hydride-Transfer Reactions of NADH/NAD+ Analogues in Solution: Reaction Center Rigidity Is the Key. Organic Letters 2020, 22 (15) , 5963-5967. https://doi.org/10.1021/acs.orglett.0c02049

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