Mispairing of a site specific major groove (2S,3S)-N6-(2,3,4- trihydroxybutyl)-2′-deoxyadenosyl DNA adduct of butadiene diol epoxide with deoxyguanosine: Formation of a dA(anti)·dG(anti) pairing interaction

Tandace A. Scholdberg, Lubomir V. Nechev, W. Keither Merritt, Thomas M. Harris, Constance M. Harris, Robert (Stephen) Lloyd, Michael P. Stone

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The (2S,3S)-N6-(2,3,4-trihydroxybutyl)-2′-deoxyadenosyl (BDT) adduct arising from alkylation of adenine N6 by butadiene diol epoxide (BDE) was placed opposite a mismatched deoxyguanosine nucleotide in the complementary strand of the oligodeoxynucleotide 5′-d(CGGACXAGAAG)- 3′-5′-d(CTTCTGGTCCG)-3′. This oligodeoxynucleotide contains codon 61 (underlined) of the human N-ras protooncogene. The BDT adduct was at the second position of codon 61, and this was named the ras61 S,S-BDT-(61,2) A·G adduct. NMR spectroscopy revealed the presence of two conformations of the adducted mismatched duplex. In the major conformation, the mismatched base pair X6·G17 was oriented in a "face-to-face" orientation, in which both the modified nucleotide X6 and its complement G17 were intrahelical and in the anti conformation about the glycosyl bond. Hydrogen bonding was suggested between X6 N1 and G17 N1H and between X6 N 6H and G17 O6. The presence of the BDT moiety allowed formation of a stable A·G mismatch pair. The identity of the minor conformation could not be determined. If not repaired, the resulting mismatch pair would generate A→C mutations, which have been associated with this adenine N6 BDT adduct [Carmical, J. R., Nechev, L. N., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Env. Mol. Mutagen. 35, 48-56].

Original languageEnglish (US)
Pages (from-to)145-153
Number of pages9
JournalChemical Research in Toxicology
Volume18
Issue number2
DOIs
StatePublished - Feb 2005

Fingerprint

Deoxyguanosine
DNA Adducts
Epoxy Compounds
Conformations
Oligodeoxyribonucleotides
Adenine
Codon
Nucleotides
Chemical bonds
Alkylation
Mutagens
Hydrogen Bonding
Base Pairing
Nuclear magnetic resonance spectroscopy
Hydrogen bonds
Magnetic Resonance Spectroscopy
1,3-butadiene
N-((2,3-dihydro-1,4-benzodioxin-2-yl)methyl)-5-methoxy-1H-indole-3-ethanamine
Mutation

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Mispairing of a site specific major groove (2S,3S)-N6-(2,3,4- trihydroxybutyl)-2′-deoxyadenosyl DNA adduct of butadiene diol epoxide with deoxyguanosine : Formation of a dA(anti)·dG(anti) pairing interaction. / Scholdberg, Tandace A.; Nechev, Lubomir V.; Merritt, W. Keither; Harris, Thomas M.; Harris, Constance M.; Lloyd, Robert (Stephen); Stone, Michael P.

In: Chemical Research in Toxicology, Vol. 18, No. 2, 02.2005, p. 145-153.

Research output: Contribution to journalArticle

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title = "Mispairing of a site specific major groove (2S,3S)-N6-(2,3,4- trihydroxybutyl)-2′-deoxyadenosyl DNA adduct of butadiene diol epoxide with deoxyguanosine: Formation of a dA(anti)·dG(anti) pairing interaction",
abstract = "The (2S,3S)-N6-(2,3,4-trihydroxybutyl)-2′-deoxyadenosyl (BDT) adduct arising from alkylation of adenine N6 by butadiene diol epoxide (BDE) was placed opposite a mismatched deoxyguanosine nucleotide in the complementary strand of the oligodeoxynucleotide 5′-d(CGGACXAGAAG)- 3′-5′-d(CTTCTGGTCCG)-3′. This oligodeoxynucleotide contains codon 61 (underlined) of the human N-ras protooncogene. The BDT adduct was at the second position of codon 61, and this was named the ras61 S,S-BDT-(61,2) A·G adduct. NMR spectroscopy revealed the presence of two conformations of the adducted mismatched duplex. In the major conformation, the mismatched base pair X6·G17 was oriented in a {"}face-to-face{"} orientation, in which both the modified nucleotide X6 and its complement G17 were intrahelical and in the anti conformation about the glycosyl bond. Hydrogen bonding was suggested between X6 N1 and G17 N1H and between X6 N 6H and G17 O6. The presence of the BDT moiety allowed formation of a stable A·G mismatch pair. The identity of the minor conformation could not be determined. If not repaired, the resulting mismatch pair would generate A→C mutations, which have been associated with this adenine N6 BDT adduct [Carmical, J. R., Nechev, L. N., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Env. Mol. Mutagen. 35, 48-56].",
author = "Scholdberg, {Tandace A.} and Nechev, {Lubomir V.} and Merritt, {W. Keither} and Harris, {Thomas M.} and Harris, {Constance M.} and Lloyd, {Robert (Stephen)} and Stone, {Michael P.}",
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T1 - Mispairing of a site specific major groove (2S,3S)-N6-(2,3,4- trihydroxybutyl)-2′-deoxyadenosyl DNA adduct of butadiene diol epoxide with deoxyguanosine

T2 - Formation of a dA(anti)·dG(anti) pairing interaction

AU - Scholdberg, Tandace A.

AU - Nechev, Lubomir V.

AU - Merritt, W. Keither

AU - Harris, Thomas M.

AU - Harris, Constance M.

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AU - Stone, Michael P.

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AB - The (2S,3S)-N6-(2,3,4-trihydroxybutyl)-2′-deoxyadenosyl (BDT) adduct arising from alkylation of adenine N6 by butadiene diol epoxide (BDE) was placed opposite a mismatched deoxyguanosine nucleotide in the complementary strand of the oligodeoxynucleotide 5′-d(CGGACXAGAAG)- 3′-5′-d(CTTCTGGTCCG)-3′. This oligodeoxynucleotide contains codon 61 (underlined) of the human N-ras protooncogene. The BDT adduct was at the second position of codon 61, and this was named the ras61 S,S-BDT-(61,2) A·G adduct. NMR spectroscopy revealed the presence of two conformations of the adducted mismatched duplex. In the major conformation, the mismatched base pair X6·G17 was oriented in a "face-to-face" orientation, in which both the modified nucleotide X6 and its complement G17 were intrahelical and in the anti conformation about the glycosyl bond. Hydrogen bonding was suggested between X6 N1 and G17 N1H and between X6 N 6H and G17 O6. The presence of the BDT moiety allowed formation of a stable A·G mismatch pair. The identity of the minor conformation could not be determined. If not repaired, the resulting mismatch pair would generate A→C mutations, which have been associated with this adenine N6 BDT adduct [Carmical, J. R., Nechev, L. N., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Env. Mol. Mutagen. 35, 48-56].

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