Computational Investigation into the Oxidation of Guanine to Form Imidazolone (Iz) and Related Degradation Products.

Imidazolone (Iz) is one of the many products resulting from oxidative damage to DNA. Three pathways for the formation of Iz and related degradation products have been studied by density functional theory using the ωB97XD functional with the 6-31+G(d,p) basis set and SMD implicit water solvation plus a small number of explicit water molecules positioned to help stabilize charged species and facilitate reaction steps. The first pathway starts with guanine radical and the addition of superoxide at C5. Endoperoxide formation was calculated to have slightly lower barriers than diol formation. The next steps are pyrimidine ring opening and decarboxylation. Ring migration then proceeds via an acyclic intermediate rather than a bicyclic intermediate and is followed by formamide loss to yield Iz. The second pathway starts with 8oxoG and proceeds via C5 superoxide addition and diol formation to a relatively stable intermediate, oxidized guanidinohydantoin (Gh). The barriers for hydroxide ion addition to Gh are much lower than for water addition and should yield more Iz and parabanic acid at higher pH. The third pathway starts with 8-hydroxy guanine radical formed by hydroxyl radical addition to C8 of guanine or water addition to C8 of guanine radical. Superoxide addition at C5 is followed by diol formation, ring opening and decarboxylation similar to pathways 1 and 2, subsequently leading to Iz formation. The calculated pathways are in good agreement with experimental observations.