The cross-link dG-to-dG is an important product of DNA nitrosation. Its formation has commonly been attributed to nucleophilic substitution of N2 in a guaninediazonium ion by guanine, while recent studies suggest guanine addition to a cyanoamine derivative formed after dediazoniation, deprotonation, and pyrimidine ring-opening. The chemical viability of the latter mechanism is supported here by the experimental demonstration of rG-to-aG formation via rG addition to a synthetic cyanoamine derivative. Thus, all known products of nitrosative guanine deamination are consistent with the postulate of pyrimidine ring-opening. This postulated mechanism not only explains what is already known but also suggests that other products and other cross-links also might be formed in DNA deamination. The study suggests one possible new product: the structure isomer aG(N1)-to-rG(C2) of the classical G(N2)-to-G(C2) cross-link. While the formation of aG(N2)-to-rG(C2) has been established by chemical synthesis, the structure isomer aG(N1)-to-rG(C2) has been assigned tentatively based on its MS/MS spectrum and because this assignment is reasonable from a mechanistic perspective. Density functional calculations show preferences for the amide-iminol tautomer of the classical cross-link G(N2)-to-G(C2) and the amide-amide tautomer of G(N1)-to-G(C2). Moreover, the results suggest that both cross-links are of comparable thermodynamic stability, and that there are no a priori energetic or structural reasons that would prevent the formation of the structure isomer in the model reaction or in DNA.
- Crosslinking,
- Isomers,
- Nitrogen Compounds,
- Structure (Composition),
- Substitution Reactions,
- Synthesis (Chemical),
- Thermodynamic Stability,
- Deamination,
- Deprotonation,
- DNA Nitrosation,
- Pyrimidine Ring-Opening,
- DNA,
- Amide,
- Diazonium Compound,
- Guanidine Derivative,
- Guanine,
- Nitrile,
- Pyrimidine,
- Cross Linking,
- Density Functional Theory,
- Isomer,
- Mass Spectrometry,
- Nitrosation,
- Reaction Analysis,
- Ring Opening,
- Synthesis,
- Thermodynamics,
- Thermostability,
- Amines,
- Aminoimidazole Carboxamide,
- Guanosine,
- Models,
- Molecular,
- Oligonucleotides,
- Ribonucleosides
Available at: http://works.bepress.com/rainer-glaser/50/