title: Demonstration of an alternative mechanism for G-to-G cross-link formation.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Missouri-Columbia, 605 South College Avenue, Columbia, Missouri 65211, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Qian
authors.forename: Rainer
authors.initials: R
authors.lastname: Glaser
mesh_terms: D000241:Adenosine; D000588:Amines / Q000737:chemistry / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D013058:Mass Spectrometry; D008958:Models, Molecular; D015538:Nitrosation; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry; D012263:Ribonucleosides / Q000737:chemistry / Q000378:metabolism; D014970:Xanthines
chemical_list: D000588:Amines; D009841:Oligonucleotides; D012263:Ribonucleosides; D014970:Xanthines; D006151:Guanosine; C008184:isoguanosine; D000620:Aminoimidazole Carboxamide; C032886:oxanosine; C031340:imidazolecarboxamide; D004247:DNA; C005893:xanthosine; D000241:Adenosine