Structural perturbations induced by the α-anomer of the aflatoxin B1 formamidopyrimidine adduct in duplex and single-strand DNA

Kyle L. Brown, Markus W. Voehler, Shane M. Magee, Constance M. Harris, Thomas M. Harris, Michael P. Stone

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The guanine N7 adduct of aflatoxin B1 exo-8,9-epoxide hydrolyzes to form the formamidopyrimidine (AFB-FAPY) adduct, which interconverts between R and β anomers. The β anomer is highly mutagenic in Escherichia coli, producing G → T transversions; it thermally stabilizes the DNA duplex. The AFB-α-FAPY adduct blocks replication; it destabilizes the DNA duplex. Herein, the structure of the AFB-α-FAPY adduct has been elucidated in 5′-d(C1T2A3T4X 5A6T7T8C9A 10)-3′ •5′-d(T11G12A 13A14T15C16A17T 18A19G20)-3′ (X = AFB-α-FAPY) using molecular dynamics calculations restrained by NMR-derived distances and torsion angles. The AFB moiety intercalates on the 5′ face of the pyrimidine moiety at the damaged nucleotide between base pairs T4 •A 17 and X5 •C16, placing the FAPY C5-N 5 bond in the Ra axial conformation. Large perturbations of the ε and ζ backbone torsion angles are observed, and the base stacking register of the duplex is perturbed. The deoxyribose orientation shifts to become parallel to the FAPY base and displaced toward the minor groove. Intrastrand stacking between the AFB moiety and the 5′ neighbor thymine remains, but strong interstrand stacking is not observed. A hydrogen bond between the formyl group and the exocyclic amine of the 3′-neighbor adenine stabilizes the E conformation of the formamide moiety. NMR studies reveal a similar 5′-intercalation of the AFB moiety for the AFB-β-FAPY adduct in the tetramer 5′-d(C1T 2X3A4)-3′, involving the Ra axial conformation of the FAPY C5-N5 bond and the E conformation of the formamide moiety. Since in duplex DNA the AFB moiety of the AFB-β-FAPY adduct also intercalates on the 5′ side of the pyrimidine moiety at the damaged nucleotide, we conclude that favorable 5′-stacking leads to the Ra conformational preference about the C5-N5 bond; the same conformational preference about this bond is also observed at the nucleoside and base levels. The structural distortions and the less favorable stacking interactions induced by the AFB-α-FAPY adduct explain its lower stability as compared to the AFB-β-FAPY adduct in duplex DNA. In this DNA sequence, hydrogen bonding between the formyl oxygen and the exocyclic amine of the 3′-neighboring adenine stabilizing the E configuration of the formamide moiety is also observed for the AFB-β-FAPY adduct, and suggests that the identity of the 3′-neighbor nucleotide modulates the stability and biological processing of AFB adducts.

Original languageEnglish (US)
Pages (from-to)16096-16107
Number of pages12
JournalJournal of the American Chemical Society
Volume131
Issue number44
DOIs
StatePublished - 2009
Externally publishedYes

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Aflatoxins
Conformations
DNA
Nucleotides
Adenine
Torsional stress
Amines
Hydrogen bonds
Nuclear magnetic resonance
Deoxyribose
A 17
Aflatoxin B1
Thymine
Chemical bonds
DNA sequences
Epoxy Compounds
Guanine
Molecular Dynamics Simulation
Hydrogen Bonding
Intercalation

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Structural perturbations induced by the α-anomer of the aflatoxin B1 formamidopyrimidine adduct in duplex and single-strand DNA. / Brown, Kyle L.; Voehler, Markus W.; Magee, Shane M.; Harris, Constance M.; Harris, Thomas M.; Stone, Michael P.

In: Journal of the American Chemical Society, Vol. 131, No. 44, 2009, p. 16096-16107.

Research output: Contribution to journalArticle

Brown, Kyle L. ; Voehler, Markus W. ; Magee, Shane M. ; Harris, Constance M. ; Harris, Thomas M. ; Stone, Michael P. / Structural perturbations induced by the α-anomer of the aflatoxin B1 formamidopyrimidine adduct in duplex and single-strand DNA. In: Journal of the American Chemical Society. 2009 ; Vol. 131, No. 44. pp. 16096-16107.
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title = "Structural perturbations induced by the α-anomer of the aflatoxin B1 formamidopyrimidine adduct in duplex and single-strand DNA",
abstract = "The guanine N7 adduct of aflatoxin B1 exo-8,9-epoxide hydrolyzes to form the formamidopyrimidine (AFB-FAPY) adduct, which interconverts between R and β anomers. The β anomer is highly mutagenic in Escherichia coli, producing G → T transversions; it thermally stabilizes the DNA duplex. The AFB-α-FAPY adduct blocks replication; it destabilizes the DNA duplex. Herein, the structure of the AFB-α-FAPY adduct has been elucidated in 5′-d(C1T2A3T4X 5A6T7T8C9A 10)-3′ •5′-d(T11G12A 13A14T15C16A17T 18A19G20)-3′ (X = AFB-α-FAPY) using molecular dynamics calculations restrained by NMR-derived distances and torsion angles. The AFB moiety intercalates on the 5′ face of the pyrimidine moiety at the damaged nucleotide between base pairs T4 •A 17 and X5 •C16, placing the FAPY C5-N 5 bond in the Ra axial conformation. Large perturbations of the ε and ζ backbone torsion angles are observed, and the base stacking register of the duplex is perturbed. The deoxyribose orientation shifts to become parallel to the FAPY base and displaced toward the minor groove. Intrastrand stacking between the AFB moiety and the 5′ neighbor thymine remains, but strong interstrand stacking is not observed. A hydrogen bond between the formyl group and the exocyclic amine of the 3′-neighbor adenine stabilizes the E conformation of the formamide moiety. NMR studies reveal a similar 5′-intercalation of the AFB moiety for the AFB-β-FAPY adduct in the tetramer 5′-d(C1T 2X3A4)-3′, involving the Ra axial conformation of the FAPY C5-N5 bond and the E conformation of the formamide moiety. Since in duplex DNA the AFB moiety of the AFB-β-FAPY adduct also intercalates on the 5′ side of the pyrimidine moiety at the damaged nucleotide, we conclude that favorable 5′-stacking leads to the Ra conformational preference about the C5-N5 bond; the same conformational preference about this bond is also observed at the nucleoside and base levels. The structural distortions and the less favorable stacking interactions induced by the AFB-α-FAPY adduct explain its lower stability as compared to the AFB-β-FAPY adduct in duplex DNA. In this DNA sequence, hydrogen bonding between the formyl oxygen and the exocyclic amine of the 3′-neighboring adenine stabilizing the E configuration of the formamide moiety is also observed for the AFB-β-FAPY adduct, and suggests that the identity of the 3′-neighbor nucleotide modulates the stability and biological processing of AFB adducts.",
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T1 - Structural perturbations induced by the α-anomer of the aflatoxin B1 formamidopyrimidine adduct in duplex and single-strand DNA

AU - Brown, Kyle L.

AU - Voehler, Markus W.

AU - Magee, Shane M.

AU - Harris, Constance M.

AU - Harris, Thomas M.

AU - Stone, Michael P.

PY - 2009

Y1 - 2009

N2 - The guanine N7 adduct of aflatoxin B1 exo-8,9-epoxide hydrolyzes to form the formamidopyrimidine (AFB-FAPY) adduct, which interconverts between R and β anomers. The β anomer is highly mutagenic in Escherichia coli, producing G → T transversions; it thermally stabilizes the DNA duplex. The AFB-α-FAPY adduct blocks replication; it destabilizes the DNA duplex. Herein, the structure of the AFB-α-FAPY adduct has been elucidated in 5′-d(C1T2A3T4X 5A6T7T8C9A 10)-3′ •5′-d(T11G12A 13A14T15C16A17T 18A19G20)-3′ (X = AFB-α-FAPY) using molecular dynamics calculations restrained by NMR-derived distances and torsion angles. The AFB moiety intercalates on the 5′ face of the pyrimidine moiety at the damaged nucleotide between base pairs T4 •A 17 and X5 •C16, placing the FAPY C5-N 5 bond in the Ra axial conformation. Large perturbations of the ε and ζ backbone torsion angles are observed, and the base stacking register of the duplex is perturbed. The deoxyribose orientation shifts to become parallel to the FAPY base and displaced toward the minor groove. Intrastrand stacking between the AFB moiety and the 5′ neighbor thymine remains, but strong interstrand stacking is not observed. A hydrogen bond between the formyl group and the exocyclic amine of the 3′-neighbor adenine stabilizes the E conformation of the formamide moiety. NMR studies reveal a similar 5′-intercalation of the AFB moiety for the AFB-β-FAPY adduct in the tetramer 5′-d(C1T 2X3A4)-3′, involving the Ra axial conformation of the FAPY C5-N5 bond and the E conformation of the formamide moiety. Since in duplex DNA the AFB moiety of the AFB-β-FAPY adduct also intercalates on the 5′ side of the pyrimidine moiety at the damaged nucleotide, we conclude that favorable 5′-stacking leads to the Ra conformational preference about the C5-N5 bond; the same conformational preference about this bond is also observed at the nucleoside and base levels. The structural distortions and the less favorable stacking interactions induced by the AFB-α-FAPY adduct explain its lower stability as compared to the AFB-β-FAPY adduct in duplex DNA. In this DNA sequence, hydrogen bonding between the formyl oxygen and the exocyclic amine of the 3′-neighboring adenine stabilizing the E configuration of the formamide moiety is also observed for the AFB-β-FAPY adduct, and suggests that the identity of the 3′-neighbor nucleotide modulates the stability and biological processing of AFB adducts.

AB - The guanine N7 adduct of aflatoxin B1 exo-8,9-epoxide hydrolyzes to form the formamidopyrimidine (AFB-FAPY) adduct, which interconverts between R and β anomers. The β anomer is highly mutagenic in Escherichia coli, producing G → T transversions; it thermally stabilizes the DNA duplex. The AFB-α-FAPY adduct blocks replication; it destabilizes the DNA duplex. Herein, the structure of the AFB-α-FAPY adduct has been elucidated in 5′-d(C1T2A3T4X 5A6T7T8C9A 10)-3′ •5′-d(T11G12A 13A14T15C16A17T 18A19G20)-3′ (X = AFB-α-FAPY) using molecular dynamics calculations restrained by NMR-derived distances and torsion angles. The AFB moiety intercalates on the 5′ face of the pyrimidine moiety at the damaged nucleotide between base pairs T4 •A 17 and X5 •C16, placing the FAPY C5-N 5 bond in the Ra axial conformation. Large perturbations of the ε and ζ backbone torsion angles are observed, and the base stacking register of the duplex is perturbed. The deoxyribose orientation shifts to become parallel to the FAPY base and displaced toward the minor groove. Intrastrand stacking between the AFB moiety and the 5′ neighbor thymine remains, but strong interstrand stacking is not observed. A hydrogen bond between the formyl group and the exocyclic amine of the 3′-neighbor adenine stabilizes the E conformation of the formamide moiety. NMR studies reveal a similar 5′-intercalation of the AFB moiety for the AFB-β-FAPY adduct in the tetramer 5′-d(C1T 2X3A4)-3′, involving the Ra axial conformation of the FAPY C5-N5 bond and the E conformation of the formamide moiety. Since in duplex DNA the AFB moiety of the AFB-β-FAPY adduct also intercalates on the 5′ side of the pyrimidine moiety at the damaged nucleotide, we conclude that favorable 5′-stacking leads to the Ra conformational preference about the C5-N5 bond; the same conformational preference about this bond is also observed at the nucleoside and base levels. The structural distortions and the less favorable stacking interactions induced by the AFB-α-FAPY adduct explain its lower stability as compared to the AFB-β-FAPY adduct in duplex DNA. In this DNA sequence, hydrogen bonding between the formyl oxygen and the exocyclic amine of the 3′-neighboring adenine stabilizing the E configuration of the formamide moiety is also observed for the AFB-β-FAPY adduct, and suggests that the identity of the 3′-neighbor nucleotide modulates the stability and biological processing of AFB adducts.

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