DNA Sequence Modulates Geometrical Isomerism of the trans-8,9- Dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)- 9-hydroxy Aflatoxin B1 Adduct.
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ABSTRACT: Aflatoxin B(1) (AFB(1)), a mycotoxin produced by Aspergillus flavus, is oxidized by cytochrome P450 enzymes to aflatoxin B(1)-8,9-epoxide, which alkylates DNA at N7-dG. Under basic conditions, this N7-dG adduct rearranges to yield the trans-8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxy aflatoxin B(1) (AFB(1)?FAPY) adduct. The AFB(1)?FAPY adduct exhibits geometrical isomerism involving the formamide moiety. NMR analyses of duplex oligodeoxynucleotides containing the 5?-XA-3?, 5?-XC-3?, 5?-XT-3?, and 5?-XY-3? sequences (X = AFB(1)?FAPY; Y = 7-deaza-dG)demonstrate that the equilibrium between E and Z isomers is controlled by major groove hydrogen bonding interactions.Structural analysis of the adduct in the 5?-XA-3? sequence indicates the preference of the E isomer of the formamide group,attributed to formation of a hydrogen bond between the formyl oxygen and the N(6) exocyclic amino group of the 3?-neighboradenine. While the 5?-XA-3? sequence exhibits the E isomer, the 5?-XC-3? sequence exhibits a 7:3 E:Z ratio at equilibrium at 283K. The E isomer is favored by a hydrogen bond between the formyl oxygen and the N(4)-dC exocyclic amino group of the 3?-neighbor cytosine. The 5?-XT-3? and 5?-XY-3? sequences cannot form such a hydrogen bond between the formyl oxygen and the 3?-neighbor T or Y, respectively, and in these sequence contexts the Z isomer is favored. Additional equilibria between ? and ? anomers and the potential to exhibit atropisomers about the C5?N(5) bond do not depend upon sequence. In each of the four DNA sequences, the AFB(1)?FAPY adduct maintains the ? deoxyribose configuration. Each of these four sequences feature the atropisomer of the AFB(1) moiety that is intercalated above the 5?-face of the damaged guanine. This enforces the Ra axialc onformation for the C5?N(5) bond.
SUBMITTER: Li L
PROVIDER: S-EPMC4332041 | biostudies-literature | 2015 Feb
REPOSITORIES: biostudies-literature
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