Proposal of alternative pathway of the glycosidic bond cleavage mechanism of 8-oxoguanosine catalyzed by the human DNA repair protein hOGG1
Jakub Šebera1, Lukáš Trantírek2, Yoshiyuki Tanaka3, Vladimír Sychrovský1
1Institute
of Organic Chemistry and Biochemistry, Flemingovo nám. 2, 166 37
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
The enzymes repairing chemically damaged DNA molecules are crucial for maintaining integrity of genetic information. One of the frequently occurring DNA mutations is the oxidative damage of nucleic acid bases that can be initiated by reactive oxygen species, ionizing radiation, and also by free organic radicals. The product of oxidation of guanine base, the 7,8-dihydro-8-oxoguanine (oxoG), can be mispaired with adenine what may have serious consequences in DNA replication. To eradicate the lesions such as oxoG and restore original DNA cell evolved base excision-repair pathways. The 8-oxoguanosine glycosylase (OGG1) is an enzyme designed for excision of oxoG in eukaryotes. Several reaction pathways were suggested and investigated theoretically during past decade based on the structural information derived from crystals of oxoG captured in catalytic pocket of hOGG1 enzyme. We come up with theoretical model of new alternative pathway for the oxoG excision that is coherent with the structural information in crystals. In order to obtain reliable picture of the glycosidic bond cleavage we confront energetic of the new reaction pathway with those for other suggested mechanisms.
This work was supported by the Young Investigator’s Grant of the Human Frontier Science Program (HFSP).