Reaction Mechanism for the N-Glycosidic Bond Cleavage of 5-Formylcytosine by Thymine DNA GlycosylaseClick to copy article linkArticle link copied!
- Eli NaydenovaEli NaydenovaChair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstr. 7, D-81377 Munich, GermanyCenter for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstr. 5-13, D-81377 Munich, GermanyMore by Eli Naydenova
- Johannes C. B. DietschreitJohannes C. B. DietschreitChair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstr. 7, D-81377 Munich, GermanyCenter for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstr. 5-13, D-81377 Munich, GermanyMore by Johannes C. B. Dietschreit
- Christian Ochsenfeld*Christian Ochsenfeld*E-mail: [email protected]. Phone: +49 89 2180 77921.Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstr. 7, D-81377 Munich, GermanyCenter for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstr. 5-13, D-81377 Munich, GermanyMore by Christian Ochsenfeld
Abstract

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.
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This article is cited by 9 publications.
- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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https://doi.org/10.1002/wcms.1471
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