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Title page for ETD etd-08052014-115231

Type of Document Dissertation
Author Li, Liang
Author's Email Address liang.li@vanderbilt.edu
URN etd-08052014-115231
Title Sequence dependence of structural perturbations to DNA induced by aflatoxin B1 formamidopyrimidine lesions
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Michael P. Stone Committee Chair
Brian O Bachmann Committee Member
Carmelo J Rizzo Committee Member
Frederick P Guengerich Committee Member
  • Geometrical isomer
  • Aflatoxin
Date of Defense 2014-07-08
Availability unrestricted
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-FAPY) adduct. This 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 of the AFB1-FAPY adduct is controlled by major groove hydrogen bonding interactions. Structural analysis of the AFB1-FAPY adduct in the 5′-XA-3′ sequence indicates the preference of the (E) geometrical isomer of the formyl group, which is attributed to formation of a hydrogen bond between the AFB1-FAPY formyl group and the N6 exocyclic amino group of the 3ʹ-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 stabilized by the formation of a hydrogen bond between the formyl group and the N4-dC exocyclic amino group of the 3'-neighbor cytosine. In contrast, the 5′-XT-3′ and 5′-XY-3′ sequences cannot form such a hydrogen bond between the formyl group and the 3′-neighbor T or Y, respectively, and the (Z) geometrical isomer is favored. In contrast, the equilibria between alpha and beta anomers of the AFB1-FAPY adduct and the potential for atropisomerism about the C5-N5 bond do not depend upon sequence. Each of these four sequences features the AFB1 moiety intercalated above the 5'-face of the damaged base. This enforces the Ra axial conformation for the C5-N5 bond. Each of the four AFB1-FAPY adducts maintains the beta deoxyribose anomeric configuration.
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