Mechanistic clues to the mutagenicity of alkylated DNA bases: a theoretical study |
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Authors: | R H Duncan G S Davies |
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Affiliation: | Department of Chemistry, Indian Institute of Technology, Madras. |
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Abstract: | Experiment indicates that the N7-guanine site in DNA is not "promutagenic" (mutation-inducing) on alkylation, while the O6-guanine and O4-thymine sites are so. These differences in nucleic acid template activity are attributed to corresponding differences in acidity of the Watson-Crick hydrogen bonding protons. Mechanistic indicators for ease of Watson-Crick proton loss are calculated using molecular orbital theory for DNA bases alkylated at the N7-guanine, O6-guanine and O4-thymine sites. Their values point to a definite favouring of the proton loss for the O-alkylated bases compared to the N7-alkylguanines. This may suggest the possibility that, at biological pH, the O-alkylated bases deprotonate readily while the N7-alkylguanines do not, thus accounting for observed differences in promutagenicity and nucleic acid template activity. |
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