烷基化DNA碱基致突变性的机制线索：一项理论研究

Mechanistic clues to the mutagenicity of alkylated DNA bases: a theoretical study.

作者信息

Duncan R H, Davies G S

机构信息

Department of Chemistry, Indian Institute of Technology, Madras.

出版信息

J Theor Biol. 1989 Oct 9;140(3):345-54. doi: 10.1016/s0022-5193(89)80091-8.

DOI:10.1016/s0022-5193(89)80091-8

PMID:2559256

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.

摘要

实验表明，DNA中的N7-鸟嘌呤位点在烷基化时并非“促诱变的”（诱导突变的），而O6-鸟嘌呤和O4-胸腺嘧啶位点则是。核酸模板活性的这些差异归因于沃森-克里克氢键合质子酸度的相应差异。使用分子轨道理论对在N7-鸟嘌呤、O6-鸟嘌呤和O4-胸腺嘧啶位点烷基化的DNA碱基计算沃森-克里克质子损失难易程度的机理指标。它们的值表明，与N7-烷基鸟嘌呤相比，O-烷基化碱基明显更有利于质子损失。这可能暗示了一种可能性，即在生理pH值下，O-烷基化碱基很容易去质子化，而N7-烷基鸟嘌呤则不会，从而解释了观察到的促诱变活性和核酸模板活性的差异。