The activation of N-glycosidic bond cleavage operated by hOGG1 enzyme can be specifically controlled by electrophilicity/nucleophilicity of the glycosidic nitrogen of normal/damaged nucleosides

Jakub Šebera1, Lukáš Trantírek2, Yoshiyuki Tanaka3, Radim Nencka1, Jiří Fukal1 and Vladimír Sychrovský1*

1Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Fleming squere 2, 166 10 Prague, Czech Republic,

2Central European Institute of Technology – Masaryk University, Kamenice 753/5, 625 00 Brno, Czech Republic,

3Division of Pharmaceutical Chemistry, Tohoku University, Aobayama, Aoba-ku, Sendai, Miyagi, 980-8578, Japan

*Corresponding author:


The role of lysine 249 (Lys 249) residue of base-excision repair enzyme hOGG1 in activation of N-glycosidic bond cleavage was studied by means of theoretical computations for 2′-deoxyguanosine (G), 8-oxo-2'-deoxyguanosine (OxoG) and N6-(2-β-D-deoxyribofuranosyl)-2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG). The interaction sites of Lys 249 involved C1’, N3, and N9 atoms of nucleosides that can be foreseen from available crystal structures.

The mechanistic pathway of nucleobase excision involving attack of lone-pair electrons at glycosidic nitrogen N9 to Ne-ammonium of Lys 249 resulted in specific activation of normal (G) and damaged (OxoG, FapyG) nucleosides owing to distinct electrophilic or nucleophilic character of the glycosidic nitrogen of normal and damaged nucleosides. Other pathways involving interaction of Lys 249 with N3 and C1’ atoms in that regard appeared unspecific.

The chemical modification of normal G owing to damage resulted in alternation of electronic character of glycosidic nitrogen, strengthening of the C1’-N9 glycosidic bond and decrease of the aromatic character of five-membered ring of nucleobase. Particularly the nucleophilicity/electrophilicity of N9 seems to control specifically proton addition to nucleobase during its excision via deprotonation of Ne-ammonium of Lys 249. The check-point mechanism proposed theoretically is coherent with base-specific enzymatic repair of G, OxoG, and FapyG that was observed experimentally.

The activation operated by attack of lone-pair electrons at glycosidic nitrogen to Ne-ammonium of Lys 249 was efficient and specific with respect to normal and damaged nucleosides owing to electrophilicity (G)/nucleophilicity (OxoG, FapyG) of glycosidic nitrogen and owing to corrupted catalytic core that was obtained specifically only for the damaged nucleosides. The glycosidic nitrogen of OxoG and FapyG can donate lone-pair electrons capable of interaction with proton of Ne-ammonium of Lys 249 while highly delocalized lone-pair electrons at N9 of G can’t interact efficiently with Ne-ammonium. The Lys 249 therefore seems to be not only key catalytic residue, but also the residue that is involved in recognition of damaged nucleobases.


Šebera, Trantirek, Tanaka, Sychrovský, J. Phys. Chem. B 2012, 116, 12535-12544. 

Šebera, Trantírek, Tanaka, Nencka, Fukal, Sychrovsky, RSC Advances 2014, 4, 83, 44043 – 44051.