title: 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.
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 α and β 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 β 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.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Brown
authors.forename: Ruidan
authors.initials: R
authors.lastname: Ma
authors.forename: Michael P
authors.initials: MP
authors.lastname: Stone
mesh_terms: D016604:Aflatoxin B1 / Q000031:analogs & derivatives* / Q000737:chemistry*; D001483:Base Sequence; D003562:Cytidine / Q000031:analogs & derivatives* / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013237:Stereoisomerism
chemical_list: C000611057:8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B1; D003562:Cytidine; D004247:DNA; D016604:Aflatoxin B1