Quantum chemistry study of repairing function of hOGG1 enzyme

Jakub Šebera¹, Lukáš Trantírek², Yoshiyuki Tanaka³, Vladimír Sychrovský¹

¹Institute of Organic Chemistry and Biochemistry, Flemingovo nám. 2, 166 37 Prague, Czech Republic

² Department of Chemistry, Utrecht University, NL-3584 CH Utrecht, Netherlands

³Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aoba-ku, Sendai 980-8578, Japan

Low-energy pathway for excision of 8-oxoguanine catalysed with the human 8-oxoguanine glycosylase 1 (hOGG1) is proposed by means of theoretical calculations. Initiation of the reaction proceeds via attacked glycosidic nitrogen of 8-oxo-2’-deoxyguanosine (oxoG) with Nz-ammonium group of Lysine 249 (Lys249). Notably pyramidal geometry of the glycosidic nitrogen accompanied by loss of the five-membered ring aromaticity are key markers of the reaction with significantly lower activation energy as compared to activation energies for S_N2 cleavage mechanisms employing attack of the anomeric carbon C1’ or simple dissociation of oxoG base.

This works was supported by the Young Investigator’s Grant of the Human Frontier Science Program (HFSP) and by Grant Agency of the Czech Republic P205/10/0228. The access to the MetaCentrum computing facilities is appreciated.