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Publication Abstract from PubMed

Aflatoxin B1 (AFB1), a mycotoxin produced by Aspergillus flavus, is oxidized by cytochrome P450 enzymes to aflatoxin B1-8,9-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-hydro xy aflatoxin B1 (AFB1-FAPY) adduct. The AFB1-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 = AFB1-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 N6 exocyclic amino group of the 3'-neighbor adenine. 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 283 K. The E isomer is favored by a hydrogen bond between the formyl oxygen and the N4-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 alpha and beta anomers and the potential to exhibit atropisomers about the C5-N5 bond do not depend upon sequence. In each of the four DNA sequences, the AFB1-FAPY adduct maintains the beta deoxyribose configuration. Each of these four sequences feature the atropisomer of the AFB1 moiety that is intercalated above the 5'-face of the damaged guanine. This enforces the Ra axial conformation for the C5-N5 bond.

DNA Sequence Modulates Geometrical Isomerism of the trans-8,9-Dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydro xy Aflatoxin B Adduct.,Li L, Brown KL, Ma R, Stone MP Chem Res Toxicol. 2015 Jan 14. PMID:25587868^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.