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Reaction Mechanism for the N-Glycosidic Bond Cleavage of 5-Formylcytosine by Thymine DNA Glycosylase
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    Reaction Mechanism for the N-Glycosidic Bond Cleavage of 5-Formylcytosine by Thymine DNA Glycosylase
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    • Eli Naydenova
      Eli Naydenova
      Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstr. 7, D-81377 Munich, Germany
      Center for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstr. 5-13, D-81377 Munich, Germany
    • Johannes C. B. Dietschreit
      Johannes C. B. Dietschreit
      Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstr. 7, D-81377 Munich, Germany
      Center for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstr. 5-13, D-81377 Munich, Germany
    • Christian Ochsenfeld*
      Christian Ochsenfeld
      Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstr. 7, D-81377 Munich, Germany
      Center for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstr. 5-13, D-81377 Munich, Germany
      *E-mail: [email protected]. Phone: +49 89 2180 77921.
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    The Journal of Physical Chemistry B

    Cite this: J. Phys. Chem. B 2019, 123, 19, 4173–4179
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    https://doi.org/10.1021/acs.jpcb.8b11706
    Published May 1, 2019
    Copyright © 2019 American Chemical Society

    Abstract

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    Thymine DNA glycosylase (TDG) initiates the base excision repair mechanism for the deamination and oxidation products of cytosine and 5-methylcytosine. This enzyme has a key role in epigenetic regulation, and its catalytic inactivation results in, e.g., mice embryo lethality. Here, we employ molecular dynamics simulations and quantum mechanics/molecular mechanics calculations to investigate the reaction mechanism of the TDG-catalyzed N-glycosidic bond hydrolysis of the modified base 5-formylcytosine. Our results reveal a reaction pathway, which in its first step features a reorganization of the substrate that lowers the barrier height for the subsequent C1′–N1 bond dissociation. The suggested mechanism is consistent with the experimental data, as it is not acid-catalyzed and proceeds through an oxocarbenium-like transition state. It also provides insights into the catalytic roles of the Thr197 and Asn140 residues.

    Copyright © 2019 American Chemical Society

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.8b11706.

    • MD simulations; protonation state of His151; and stabilization of the anionic base (PDF)

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    Cited By

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    This article is cited by 9 publications.

    1. Wen-Juan Wang, Tian Wang, Ying Zhao, Bi-Na Li, De-Zhan Chen. Theoretical Insights into N-Glycoside Bond Cleavage of 5-Carboxycytosine by Thymine DNA Glycosylase: A QM/MM Study. The Journal of Physical Chemistry B 2024, 128 (19) , 4621-4630. https://doi.org/10.1021/acs.jpcb.4c00221
    2. Johannes C. B. Dietschreit, Dennis J. Diestler, Rafael Gómez-Bombarelli. Entropy and Energy Profiles of Chemical Reactions. Journal of Chemical Theory and Computation 2023, 19 (16) , 5369-5379. https://doi.org/10.1021/acs.jctc.3c00448
    3. Frank Beierlein, Senta Volkenandt, Petra Imhof. Oxidation Enhances Binding of Extrahelical 5-Methyl-Cytosines by Thymine DNA Glycosylase. The Journal of Physical Chemistry B 2022, 126 (6) , 1188-1201. https://doi.org/10.1021/acs.jpcb.1c09896
    4. Ye Eun Rebecca Jeong, Stefan A. P. Lenz, Stacey D. Wetmore. DFT Study on the Deglycosylation of Methylated, Oxidized, and Canonical Pyrimidine Nucleosides in Water: Implications for Epigenetic Regulation and DNA Repair. The Journal of Physical Chemistry B 2020, 124 (12) , 2392-2400. https://doi.org/10.1021/acs.jpcb.0c00783
    5. Paul J. Sanstead, Brennan Ashwood, Qing Dai, Chuan He, Andrei Tokmakoff. Oxidized Derivatives of 5-Methylcytosine Alter the Stability and Dehybridization Dynamics of Duplex DNA. The Journal of Physical Chemistry B 2020, 124 (7) , 1160-1174. https://doi.org/10.1021/acs.jpcb.9b11511
    6. Lakshmi S. Pidugu, Qing Dai, Shuja S. Malik, Edwin Pozharski, Alexander C. Drohat. Excision of 5-Carboxylcytosine by Thymine DNA Glycosylase. Journal of the American Chemical Society 2019, 141 (47) , 18851-18861. https://doi.org/10.1021/jacs.9b10376
    7. You Lu, Kakali Sen, Chin Yong, David S. D. Gunn, John A. Purton, Jingcheng Guan, Alec Desmoutier, Jamal Abdul Nasir, Xingfan Zhang, Lei Zhu, Qing Hou, Joe Jackson-Masters, Sam Watts, Rowan Hanson, Harry N. Thomas, Omal Jayawardena, Andrew J. Logsdail, Scott M. Woodley, Hans M. Senn, Paul Sherwood, C. Richard A. Catlow, Alexey A. Sokol, Thomas W. Keal. Multiscale QM/MM modelling of catalytic systems with ChemShell. Physical Chemistry Chemical Physics 2023, 25 (33) , 21816-21835. https://doi.org/10.1039/D3CP00648D
    8. Senta Volkenandt, Frank Beierlein, Petra Imhof. Interaction of Thymine DNA Glycosylase with Oxidised 5-Methyl-cytosines in Their Amino- and Imino-Forms. Molecules 2021, 26 (19) , 5728. https://doi.org/10.3390/molecules26195728
    9. Rajwinder Kaur, Dylan J. Nikkel, Stacey D. Wetmore. Computational studies of DNA repair: Insights into the function of monofunctional DNA glycosylases in the base excision repair pathway. WIREs Computational Molecular Science 2020, 10 (5) https://doi.org/10.1002/wcms.1471

    The Journal of Physical Chemistry B

    Cite this: J. Phys. Chem. B 2019, 123, 19, 4173–4179
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jpcb.8b11706
    Published May 1, 2019
    Copyright © 2019 American Chemical Society

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