66
N. R. Jena et al.
of 8-oxoG, due to its low oxidation potential, it further reacts with O 2
•−
to form the
most stable guanine oxidation product Oz. It is found that degradation of 8-oxoG to
Oz readily occurs at neutral pH, while formation of Iz is relatively more favoured
at basic pH [120].
3.3.3 By Peroxynitrite (ONOO
−
)
It has been suggested that ONOO
−
is capable of initiating both oxidation and nitration of guanine. ONOO
−
mediated oxidation of guanine mainly generates 8-oxoG
and Oz, while its nitration produces 8-NO 2 G [61, 65, 106, 108, 109] and NI [110–
114]. However, in cellular DNA, NI has been observed to be the dominant nitration
product of guanine. A DFT study has revealed that ONOO
−
mediated oxidation of
guanine generates 8-oxoG and NO 2
−
, while nitration of guanine can yield either
8-NO 2 G
−
+ H 2 O or 8-NO 2 G + OH
−
[61]. Further, DFT studies have revealed that the
reactivity of ONOO
−
gets enhanced in the presence of carbon dioxide (CO 2 ) that
catalyses its reaction with guanine to produce 8-oxoG as discussed below [65]. A
theoretical study of the reaction of ONOO
−
with guanine in the presence of CO 2
was carried out [65] at the B3LYP/6-31G(d, p) and B3LYP/AUG-cc-pVDZ levels
of density functional theory [121, 122]. Geometry optimization calculations were
carried out in gas phase while bulk solvent effect in aqueous media was treated by
single-point energy calculations at the B3LYP/AUG-cc-pVDZ level of theory employing the polarizable continuum model (PCM) [123, 124]. An important catalytic
role was found to be played by CO 2 in the reactions of ONOO
−
with guanine as
discussed below.
Initially, ONOO
−
and CO 2 react together to form the nitrosoperoxycarbonate anion (ONOOCO 2
−
) complex and subsequently this complex reacts with guanine [65].
Certain details of this reaction are as follows (Fig. 3.3). (a) The cis-conformer of nitrosoperoxycarbonate anion is more stable than its trans-conformer by about 1 kcal/
mol. Further, the cis-conformer of nitrosoperoxycarbonate anion makes a stronger
hydrogen bonded complex with the H9 atom of guanine than its trans-conformer.
(b) The reactions between ONOOCO 2
−
and guanine occurring through different
schemes mainly produce 8-oxoG or 8-NO 2 G
−
. (c) An analysis of the structures of
products and barrier energies reveals that CO 2 acts as a catalyst in these reactions.
It is found that ONOOCO 2
−
is broken into the CO 3 radical anion and NO 2
•
due to
dissociation of the OO bond while reacting with guanine. Intermediacy of CO 3
•−
and
NO 2
•
appears to be the main cause of the catalytic action of CO 2 . (d) As revealed by
the calculated total energies of the products, 8-oxoG would be produced in much
more abundance than 8-NO 2 G
−
. Therefore, ONOO
−
in complexation with CO 2
would cause mutation mainly through the formation of 8-oxoG. (e) The bulk solvent effect of water plays an important role in reducing the reaction barrier energies.
N. R. Jena et al.
of 8-oxoG, due to its low oxidation potential, it further reacts with O 2
•−
to form the
most stable guanine oxidation product Oz. It is found that degradation of 8-oxoG to
Oz readily occurs at neutral pH, while formation of Iz is relatively more favoured
at basic pH [120].
3.3.3 By Peroxynitrite (ONOO
−
)
It has been suggested that ONOO
−
is capable of initiating both oxidation and nitration of guanine. ONOO
−
mediated oxidation of guanine mainly generates 8-oxoG
and Oz, while its nitration produces 8-NO 2 G [61, 65, 106, 108, 109] and NI [110–
114]. However, in cellular DNA, NI has been observed to be the dominant nitration
product of guanine. A DFT study has revealed that ONOO
−
mediated oxidation of
guanine generates 8-oxoG and NO 2
−
, while nitration of guanine can yield either
8-NO 2 G
−
+ H 2 O or 8-NO 2 G + OH
−
[61]. Further, DFT studies have revealed that the
reactivity of ONOO
−
gets enhanced in the presence of carbon dioxide (CO 2 ) that
catalyses its reaction with guanine to produce 8-oxoG as discussed below [65]. A
theoretical study of the reaction of ONOO
−
with guanine in the presence of CO 2
was carried out [65] at the B3LYP/6-31G(d, p) and B3LYP/AUG-cc-pVDZ levels
of density functional theory [121, 122]. Geometry optimization calculations were
carried out in gas phase while bulk solvent effect in aqueous media was treated by
single-point energy calculations at the B3LYP/AUG-cc-pVDZ level of theory employing the polarizable continuum model (PCM) [123, 124]. An important catalytic
role was found to be played by CO 2 in the reactions of ONOO
−
with guanine as
discussed below.
Initially, ONOO
−
and CO 2 react together to form the nitrosoperoxycarbonate anion (ONOOCO 2
−
) complex and subsequently this complex reacts with guanine [65].
Certain details of this reaction are as follows (Fig. 3.3). (a) The cis-conformer of nitrosoperoxycarbonate anion is more stable than its trans-conformer by about 1 kcal/
mol. Further, the cis-conformer of nitrosoperoxycarbonate anion makes a stronger
hydrogen bonded complex with the H9 atom of guanine than its trans-conformer.
(b) The reactions between ONOOCO 2
−
and guanine occurring through different
schemes mainly produce 8-oxoG or 8-NO 2 G
−
. (c) An analysis of the structures of
products and barrier energies reveals that CO 2 acts as a catalyst in these reactions.
It is found that ONOOCO 2
−
is broken into the CO 3 radical anion and NO 2
•
due to
dissociation of the OO bond while reacting with guanine. Intermediacy of CO 3
•−
and
NO 2
•
appears to be the main cause of the catalytic action of CO 2 . (d) As revealed by
the calculated total energies of the products, 8-oxoG would be produced in much
more abundance than 8-NO 2 G
−
. Therefore, ONOO
−
in complexation with CO 2
would cause mutation mainly through the formation of 8-oxoG. (e) The bulk solvent effect of water plays an important role in reducing the reaction barrier energies.