The Mechanism Of Initial Oxidative Damage Of 2'-Deoxyguanosine' By Carbonate Radical Anion

Carbonate radical anion(CO3·-)is one of the important reactive oxygen species in organisms.Because of its strong oxidizing property,the study on its oxidative damage to DNA has attracted more and more attention in recent years.The reaction mechanism of CO3·-with 2'-deoxyguanosine(2'-dGuo)has not been clarified by theoretical study so far.Therefore,in this thesis,the mechanism of initial oxidative damage of 2'-dGuo by CO3·-has been investigated using density functional theory and computational kinetics methods.Three possible reaction mechanisms have been considered:radical adduct formation(RAF),hydrogen transfer(HT)and sequential electron proton transfer(SEPT).1.The addition reaction of CO3·-at the C8 site of base moiety of 2'-dGuo is favorable,while the addition reactions of CO3·-at the C4 and C5 sites are negligible.The reaction rate constant of CO3·-addition to C8 site is 1.06x103 dm3 mol-1 s-1.Among the adduct radicals formed at C4,C5 and C8 sites,the energy of C8 site adduct radical is the lowest,and it is also the most stable.2.The hydrogen abstraction reactions between CO3·-and 2'-dGuo mainly take place on the 2'-deoxyribose moiety of 2'-dGuo.Abstracting hydrogen atom from the C5'site of 2'-deoxyribose moiety by CO3·-is the most favorable,along with a rate constant of 1.11×105 dm3 mol-1 s-1,followed from the C3' site,and the corresponding rate constant is 1.90×103 dm3 mol-1 s-1.Abstracting hydrogen atoms from the base moiety by CO3·-is difficult,and the rate constants are in the range of 1.36×10-9 to 0.16 dm3 mol-1 s-1.3.2'-dGuo is easily oxidized by CO3·-.In the SEPT mechanism,CO3·-obtains an electron from 2'-dGo forming CO32-and 2'-deoxyguanosine radical cation(2'-dGuo·+),then proton transfer takes place between C032-and 2'-dGuo·?.The terminal products are HCO3-and neutral 2'-deoxyguanosine radical(dGuo(-H)N1·),and SEPT reaction rate constant is 4.19×108 dm3 mol-1 s-1.Among the three reaction mechanisms studied,the SEPT is the most favorable reaction mechanism.The SEPT and RAF mechanisms occur on the base moiety of 2'-dGuo,and the mechanism of HT mainly takes place on the 2'-deoxyribose moiety of 2'-dGuo.During the initial oxidative damage stage of 2'-dGuo by CO3·-,the dGuo(-H)N1·is major damage intermediate,and CO3·-causes an approximately 3700-fold preference for base damage over sugar damage.The results are consistent with the experimental results.This paper systematically expounds the mechanism and kinetic process of initial oxidative damage of 2'-dGuo by CO3·-at the electronic micro level,which has important theoretical significance for the research of DNA damage induced by free radicals.