Stereospecific structural perturbations arising from adenine N(6) butadiene triol adducts in duplex DNA.

Merritt WK, Scholdberg TA, Nechev LV, Harris TM, Harris CM, Lloyd RS, Stone MP
Chem Res Toxicol. 2004 17 (8): 1007-19

PMID: 15310233 · DOI:10.1021/tx049908j

Butadiene is oxidized in vivo to form stereoisomeric butadiene diol epoxides (BDE). These react with adenine N(6) in DNA yielding stereoisomeric N(6)-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl (BDT) adducts. When replicated in Escherichia coli, the (2R,3R)-N(6)-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl adduct yielded low levels of A-->G mutations whereas the (2S,3S)-N(6)-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl butadiene triol adduct yielded low levels of A-->C mutations [Carmical, J. R., Nechev, L. V., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Environ. Mol. Mutagen. 35, 48-56]. Accordingly, the structure of the (2R,3R)-N(6)-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl adduct at position X(6) in d(CGGACXAGAAG).d(CTTCTTGTCCG), the ras61 R,R-BDT-(61,2) adduct, was compared to the corresponding structure for the (2S,3S)-N(6)-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl adduct in the same sequence, the ras61 S,S-BDT-(61,2) adduct. Both the R,R-BDT-(61,2) and S,S-BDT-(61,2) adducts are oriented in the major groove of the DNA, accompanied by modest structural perturbations. However, structural refinement of the two adducts using a simulated annealing restrained molecular dynamics (rMD) approach suggests stereospecific differences in hydrogen bonding between the hydroxyl groups located at the beta- and gamma-carbons of the BDT moiety, and T(17) O(4) of the modified base pair X(6).T(17). The rMD calculations predict hydrogen bond formation between the gamma-OH and the T(17) O(4) in the R,R-BDT-(61,2) adduct whereas in the S,S-BDT-(61,2) adduct, hydrogen bond formation is predicted between the beta-OH and the T(17) O(4). This difference positions the two adducts differently in the major groove. This may account for the differential mutagenicity of the two adducts and suggests that the two adducts may interact differentially with other DNA processing enzymes. With respect to mutagenesis in E. coli, the minimal perturbation of DNA induced by both major groove adducts correlates with their facile bypass by three E. coli DNA polymerases in vitro and may account for their weak mutagenicity [Carmical, J. R., Nechev, L. V., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Environ. Mol. Mutagen. 35, 48-56].

MeSH Terms (15)

Adenine Animals Base Sequence Butadienes Butanols DNA Adducts Epoxy Compounds Escherichia coli Magnetic Resonance Spectroscopy Molecular Sequence Data Mutagenicity Tests Nucleic Acid Heteroduplexes Protons Stereoisomerism Thermodynamics

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