posted on 2020-03-20, 14:34authored bySebastien
P. Hebert, H. Bernhard Schlegel
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 (Ghox). The barriers for hydroxide
ion addition to Ghox 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.