Demonstration of an Alternative Mechanism for G-to-G Cross-Link Formation
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.
M. Qian and R. Glaser, "Demonstration of an Alternative Mechanism for G-to-G Cross-Link Formation," Journal of the American Chemical Society, vol. 127, no. 3, pp. 880-887, American Chemical Society (ACS), Jan 2005.
The definitive version is available at https://doi.org/10.1021/ja045108j
Keywords and Phrases
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
International Standard Serial Number (ISSN)
Article - Journal
© 2005 American Chemical Society (ACS), All rights reserved.
01 Jan 2005