Ribose-Protonated DNA Base Excision Repair: A Combined Theoretical and Experimental Study†
Dr. Keyarash Sadeghian
Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstrasse 7, 81377 Munich (Germany)
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Search for more papers by this authorDr. Denis Flaig
Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstrasse 7, 81377 Munich (Germany)
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Search for more papers by this authorIris D. Blank
Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstrasse 7, 81377 Munich (Germany)
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Search for more papers by this authorDr. Sabine Schneider
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Department of Chemistry, Chair of Biochemistry, TU München, Lichtenbergstrasse 4, 85747 Garching (Germany)
Search for more papers by this authorDr. Ralf Strasser
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Search for more papers by this authorDr. Dimitrios Stathis
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Search for more papers by this authorDr. Malte Winnacker
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Search for more papers by this authorCorresponding Author
Prof. Dr. Thomas Carell
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Thomas Carell, Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Christian Ochsenfeld, Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstrasse 7, 81377 Munich (Germany)
Search for more papers by this authorCorresponding Author
Prof. Dr. Christian Ochsenfeld
Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstrasse 7, 81377 Munich (Germany)
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Thomas Carell, Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Christian Ochsenfeld, Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstrasse 7, 81377 Munich (Germany)
Search for more papers by this authorDr. Keyarash Sadeghian
Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstrasse 7, 81377 Munich (Germany)
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Search for more papers by this authorDr. Denis Flaig
Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstrasse 7, 81377 Munich (Germany)
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Search for more papers by this authorIris D. Blank
Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstrasse 7, 81377 Munich (Germany)
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Search for more papers by this authorDr. Sabine Schneider
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Department of Chemistry, Chair of Biochemistry, TU München, Lichtenbergstrasse 4, 85747 Garching (Germany)
Search for more papers by this authorDr. Ralf Strasser
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Search for more papers by this authorDr. Dimitrios Stathis
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Search for more papers by this authorDr. Malte Winnacker
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Search for more papers by this authorCorresponding Author
Prof. Dr. Thomas Carell
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Thomas Carell, Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Christian Ochsenfeld, Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstrasse 7, 81377 Munich (Germany)
Search for more papers by this authorCorresponding Author
Prof. Dr. Christian Ochsenfeld
Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstrasse 7, 81377 Munich (Germany)
Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Thomas Carell, Center for Integrated Protein Science (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich (Germany)
Christian Ochsenfeld, Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstrasse 7, 81377 Munich (Germany)
Search for more papers by this authorWe acknowledge financial support by the DFG funding initiatives SFB749 (TP A4 and C7) and the Excellence Cluster EXC114 (CIPSM).
Abstract
Living organisms protect the genome against external influences by recognizing and repairing damaged DNA. A common source of gene mutation is the oxidized guanine, which undergoes base excision repair through cleavage of the glycosidic bond between the ribose and the nucleobase of the lesion. We unravel the repair mechanism utilized by bacterial glycosylase, MutM, using quantum-chemical calculations involving more than 1000 atoms of the catalytic site. In contrast to the base-protonated pathway currently favored in the literature, we show that the initial protonation of the lesion’s ribose paves the way for an almost barrier-free glycosidic cleavage. The combination of theoretical and experimental data provides further insight into the selectivity and discrimination of MutM’s binding site toward various substrates.
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