Abstract:Numerous damages to cellular DNA are imposed by oxidative stress. Formation of stable products resulting from oxidation of nucleobases is one of many observed consequences. The oxidized species constitute a class of heterocyclic compounds with great diversities of physicochemical properties. Modified nucleosides significantly differ from their canonical protoplasts by tautomeric equilibriums, protolytic properties in the gas phase and water solution, they have altered oxidative susceptibility and N-glycosidic … Show more
“…To calculatet he activation barrier,o ne explicit water molecule has to be taken into account. Proton transfer to the N7 site (from the C8-positiona sd escribed in ap revious section) stabilizes the 8-oxo-dGMP structure (Cysewski [45] calculated pK a (N7ÀH) = 9.5) in both G_5 andG _3 reactionb ranches. Simultaneously with this PT also weakening of the PÀO8 or C5'ÀO8 bonds occurs.…”
The reduction mechanism of [Pt(IV) (dach)Cl4 ] (dach=diaminocyclohexyl) in the presence of dGMP was studied. The first step is substitution of a chloro ligand by dGMP, followed by nucleophilic attack of a phosphate or sugar oxygen atom to the C8-position of guanine. Subsequent reduction forms the [Pt(II) (dach)Cl2 ] complex. The whole process is completed by a hydrolysis. Two different pathways for the substitution reaction were examined: a direct associative and a Basolo-Pearson autocatalytic mechanism. All the explored structures were optimized at the B3LYP-D3/6-31G(d) level and by using the COSMO solvation model with Klamt's radii. Single-point energetics was determined at the B3LYP-GD3BJ/6-311++G(2df,2pd)/PCM/scaled-UAKS level. Activation barriers were used for an estimation of the rate constants and these were compared with experimental values. It was found that the rate-determining step is the nucleophilic attack with a slightly faster performance in the 3'-dGMP branch than in the case of 5'-dGMP with activation barriers of 21.1 and 20.4 kcal mol(-1) (experimental: 23.8 and 23.2 kcal mol(-1) ). The reduction reaction is connected with an electron flow from guanine. The product of the reduction reaction is a chelate structure, which dissociates within the last reaction step, that is, a hydrolysis reaction. The whole redox process (substitution, reduction, and hydrolysis) is exergonic by 34 and 28 kcal mol(-1) for 5'-dGMP and 3'-dGMP, respectively.
“…To calculatet he activation barrier,o ne explicit water molecule has to be taken into account. Proton transfer to the N7 site (from the C8-positiona sd escribed in ap revious section) stabilizes the 8-oxo-dGMP structure (Cysewski [45] calculated pK a (N7ÀH) = 9.5) in both G_5 andG _3 reactionb ranches. Simultaneously with this PT also weakening of the PÀO8 or C5'ÀO8 bonds occurs.…”
The reduction mechanism of [Pt(IV) (dach)Cl4 ] (dach=diaminocyclohexyl) in the presence of dGMP was studied. The first step is substitution of a chloro ligand by dGMP, followed by nucleophilic attack of a phosphate or sugar oxygen atom to the C8-position of guanine. Subsequent reduction forms the [Pt(II) (dach)Cl2 ] complex. The whole process is completed by a hydrolysis. Two different pathways for the substitution reaction were examined: a direct associative and a Basolo-Pearson autocatalytic mechanism. All the explored structures were optimized at the B3LYP-D3/6-31G(d) level and by using the COSMO solvation model with Klamt's radii. Single-point energetics was determined at the B3LYP-GD3BJ/6-311++G(2df,2pd)/PCM/scaled-UAKS level. Activation barriers were used for an estimation of the rate constants and these were compared with experimental values. It was found that the rate-determining step is the nucleophilic attack with a slightly faster performance in the 3'-dGMP branch than in the case of 5'-dGMP with activation barriers of 21.1 and 20.4 kcal mol(-1) (experimental: 23.8 and 23.2 kcal mol(-1) ). The reduction reaction is connected with an electron flow from guanine. The product of the reduction reaction is a chelate structure, which dissociates within the last reaction step, that is, a hydrolysis reaction. The whole redox process (substitution, reduction, and hydrolysis) is exergonic by 34 and 28 kcal mol(-1) for 5'-dGMP and 3'-dGMP, respectively.
“…While the amino form emulates the hydrogen bonding pattern of C the imino form emulates that of T(U). Theoretical calculations in the gas phase favor the amino over the keto tautomer in the neutral form ( 8 ). UV resonance Raman spectroscopy of 5-HOdC shows enhanced presence of the imino tautomer by ~100-fold compared to dC at physiological pH and temperature, which results in a frequency of occurrence of this tautomer of 0.3–0.7%.…”
Section: Discussionmentioning
confidence: 99%
“…While there is some controversy on the level of mutagenicity of the intermediates along the oxidation pathway ( 5–7 ), it has been shown in Escherichia coli that 5-HOdC itself also causes C→T transitions, however, at a significantly lower frequency ( 5 ). The mutagenicity has been associated with tautomeric variability of the oxidized base ( 7–9 ). Figure 1.…”
The synthesis of a caged RNA phosphoramidite building block containing the oxidatively damaged base 5-hydroxycytidine (5-HOrC) has been accomplished. To determine the effect of this highly mutagenic lesion on complementary base recognition and coding properties, this building block was incorporated into a 12-mer oligoribonucleotide for Tm and CD measurements and a 31-mer template strand for primer extension experiments with HIV-, AMV- and MMLV-reverse transcriptase (RT). In UV-melting experiments, we find an unusual biphasic transition with two distinct Tm's when 5-HOrC is paired against a DNA or RNA complement with the base guanine in opposing position. The higher Tm closely matches that of a C-G base pair while the lower is close to that of a C-A mismatch. In single nucleotide extension reactions, we find substantial misincorporation of dAMP and to a lesser extent dTMP, with dAMP almost equaling that of the parent dGMP in the case of HIV-RT. A working hypothesis for the biphasic melting transition does not invoke tautomeric variability of 5-HOrC but rather local structural perturbations of the base pair at low temperature induced by interactions of the 5-HO group with the phosphate backbone. The properties of this RNA damage is discussed in the context of its putative biological function.
“…Furthermore, the benzene ring can undergo large out-of-plane distortions [30][31][32][33] but its aromaticity and ring-current diamagnetism seem to be quite insensitive to such deformations of the molecule [30][31][32][33][34]. Such aromatic ring elasticity was documented as the common phenomenon not only for benzene analogues but it is also characteristic for heterocyclic compounds [27,28,35]. This is of particular importance since it provides additional degrees of freedom to biomolecules interacting in native environments.…”
The unique set of aromaticity indices was identified for thermally induced changes of π-electron delocalization by means of PCA (Principal Component Analysis). It was demonstrated that solvents polarity can influence not only the values of aromaticity indices but also their contribution to Principal Components. Therefore, in different phases one should select different indices for a proper description of the aromaticity. The found aromaticity diversities indices were provided for aniline as well as p-nitrosoaniline and it was found that the geometry of the latter one is highly sensitive to solvents polarity changes. Thus, all of the aromaticity indices experienced a reduction of their values, with the HOMA (Harmonic Oscillator Model of Aromaticity) index being the most sensitive. It was also found that there were such vibrations which could alter this trend and lead to apparent increase of aromaticity.
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