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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• 作者：Liang Li ; Kyle L. Brown ; Ruidan Ma ; Michael P. Stone
• 刊名：Chemical Research in Toxicology
• 出版年：2015
• 出版时间：February 16, 2015
• 年：2015
• 卷：28
• 期：2
• 页码：225-237
• 全文大小：540K
• ISSN：1520-5010

文摘

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-hydroxy aflatoxin B₁ (AFB₁鈥揊APY) adduct. The AFB₁鈥揊APY adduct exhibits geometrical isomerism involving the formamide moiety. NMR analyses of duplex oligodeoxynucleotides containing the 5鈥?XA-3鈥? 5鈥?XC-3鈥? 5鈥?XT-3鈥? and 5鈥?XY-3鈥?sequences (X = AFB₁鈥揊APY; 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鈥?XA-3鈥?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 Np>6p> exocyclic amino group of the 3鈥?neighbor adenine. While the 5鈥?XA-3鈥?sequence exhibits the E isomer, the 5鈥?XC-3鈥?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 Np>4p>-dC exocyclic amino group of the 3鈥?neighbor cytosine. The 5鈥?XT-3鈥?and 5鈥?XY-3鈥?sequences cannot form such a hydrogen bond between the formyl oxygen and the 3鈥?neighbor T or Y, respectively, and in these sequence contexts the Z isomer is favored. Additional equilibria between 伪 and 尾 anomers and the potential to exhibit atropisomers about the C5鈥?i>Np>5p> bond do not depend upon sequence. In each of the four DNA sequences, the AFB₁鈥揊APY adduct maintains the 尾 deoxyribose configuration. Each of these four sequences feature the atropisomer of the AFB₁ moiety that is intercalated above the 5鈥?face of the damaged guanine. This enforces the R_a axial conformation for the C5鈥?i>Np>5p> bond.