Theoretical prediction of the p53 gene mutagenic mechanism induced by trans-4-hydroxy-2-nonenal.
The reaction mechanism of guanine with trans-4-hydroxyl-2-nonenal (4-HNE) and the mutagenic mechanism induced by adducts have been theoretically predicted at a molecular level from the energy point of view. 4-HNE directly reacts with guanine via three steps, yielding eventually four main diastereoisomers: trans-4-HNE-dG adducts. A concerted six-atom-centered transition state is proposed for the first step, while the last two steps are involved in four-membered-ring transition states. The third step is the rate-determining step. The studies of base pairing properties of trans-4-HNE-dG adducts with A, T, C, A*, and T* together with the relationship between the mutation and structure of trans-4-HNE-dG indicate that syn- and anti-conformations of trans-4-HNE-dG around the glycosidic bond are favorable for pairing with A* and T*, respectively, in the parental generation. As a result, the GC --> CG or GC --> TA mutation may be generated from the syn-4-HNE-dGA* during replication. Nevertheless, anti-4-HNE-dGT* creates GC --> TA mutation or nonmutagenesis. Moreover, syn-4-HNE-dGA* has a slightly higher probability to be generated than anti-4-HNE-dGT* in the parental generation; therefore, the GC to TA transversion is predominant among the mutations. In addition, no correlation between the mutations and the stereochemistry of C6 and C8 of trans-4-HNE-dG adducts was found in this work. Our mutational results have interpreted well a part of the discrete experimental observations, but the mutagenic process itself has not previously been characterized, through either computation or experiment.
Xing
Dianxiang
D
Institute of Theoretical Chemistry, Shandong University, Jinan, 250100, People's Republic of China.
Sun
Lixiang
L
Cukier
Robert I
RI
Bu
Yuxiang
Y
D000447:Aldehydes / Q000737:chemistry*; D016158:Genes, p53 / Q000235:genetics*; D006147:Guanine / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D016296:Mutagenesis / Q000187:drug effects*; D009154:Mutation / Q000235:genetics*; D012984:Software
D000447:Aldehydes; D006147:Guanine; C027576:4-hydroxy-2-nonenal