Quantum Chemical Study on Base Excision Mechanism of 8-Oxoguanine DNA Glycosylase: Substrate-Assisted Catalysis of the N-Glycosidic Linkage Cleavage Reaction

Abstract

Human 8-oxoguanine DNA glycosylase 1(hOGG1) plays a significant role of repairing oxidized genomic DNAs. The repair process includes the cleavage reaction of N-glycosidic linkage between 8-oxoguanine (8-oxoG) and the deoxyribose. To clarify the atomic-scale reaction mechanism of the N-glycosidic linkage cleavage, quantum chemical (QM) calculation at B3LYP/6-31G(d,p) was performed with a reaction model that consists of the catalytic Lys249 and guanosine that includes the 8-oxoG. It has been found from the QM calculation that the cleavage mechanism proceeds via three elementary reactions. In the first elementary reaction, a proton in the ammonium group of Lys249 is removed by the oxygen atom of 8-oxoG (8O) in concert with the generation of a new hydrogen bond between 8O and O4' of deoxyribose. In the second elementary reaction, N atom in Lys249 side chain (Nζ) nucleophilically attacks on C1' of the deoxyribose in concert with the spontaneous proton migration from 8O to O4'. The proton migration induces the dissociation of ether bond between O4' and C1'. Finally, a proton migrates from Nζ to N9 in 8-oxoG via 8O. N-glycosidic linkage between C1' and N9 is completely cloven in the final elementary reaction. It was confirmed that Schiff base appeared in products of the final reaction. According to the obtained base excision mechanism, 8O participates in the first and second elementary reactions. Therefore, this enzymatic reaction is a substrate-assisted catalysis. It was also found that the reaction path requires large activation energy (<42kcal/mol). This result finely reflects the experimental finding that the enzymatic activity of hOGG1 is not so high.