Dual roles of glycosyl torsion angle conformation and stereochemical configuration in butadiene oxide-derived N1 β-hydroxyalkyl deoxyinosine adducts

A structural perspective

W. Keither Merritt, Agnieszka Kowalczyk, Tandace A. Scholdberg, Stephen M. Dean, Thomas M. Harris, Constance M. Harris, Robert (Stephen) Lloyd, Michael P. Stone

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The solution structure of the N1-[1-hydroxy-3-buten-2(R)-yl]-2′- deoxyinosine adduct arising from the alkylation of adenine N1 by butadiene epoxide (BDO), followed by deamination to deoxyinosine, was determined in the oligodeoxynucleotide 5′-d(CGGACXAGAAG)-3′-5′-d(CTTCTTGTCCG)- 3′. This oligodeoxynucleotide contained the BDO adduct at the second position of codon 61 of the human N-ras protooncogene (underlined) and was named the ras61 R-N1-BDO-(61,2) adduct. 1H NMR revealed a weak C 5 H1′ to X6 H8 nuclear Overhauser effects (NOE), followed by an intense X6 H8 to X6 H1′ NOE. Simultaneously, the X6 H8 to X6 H3′ NOE was weak. The resonances arising from the T16 and T17 imino protons were not observed. 1H NOEs between the butadiene moiety and the DNA positioned the adduct in the major groove. Structural refinement based upon a total of 394 NOE-derived distance restraints and 151 torsion angle restraints yielded a structure in which the modified deoxyinosine was in the syn conformation about the glycosyl bond, with a glycosyl bond angle of 83°, and T17, the complementary nucleotide, was stacked into the helix but not hydrogen bonded with the adducted inosine. The refined structure provides a plausible hypothesis as to why these N1 deoxyinosine adducts strongly code for the incorporation of dCTP during trans lesion DNA replication, irrespective of stereochemistry, both in Escherichia coli [Rodriguez, D. A., Kowalczyk, A., Ward, J. B. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2001) Environ. Mol. Mutagen. 38, 292-296] and in mammalian cells [Kanuri, M., Nechev, L. N., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572-1580]. Rotation of the N1 deoxyinosine adduct into the syn conformation may facilitate incorporation of dCTP via Hoogsteen type templating with deoxyinosine, generating A to G mutations. However, conformational differences between the R- and the S-N1-BDO-(61,2) adducts, involving the positioning of the butenyl moiety in the major groove of DNA, suggest that adduct stereochemistry plays a secondary role in modulating the biological response to these adducts.

Original languageEnglish (US)
Pages (from-to)1098-1107
Number of pages10
JournalChemical Research in Toxicology
Volume18
Issue number7
DOIs
StatePublished - Jul 2005

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Torsional stress
Conformations
Epoxy Compounds
Stereochemistry
DNA Adducts
Oligodeoxyribonucleotides
Inosine
Deamination
Alkylation
Mutagens
Adenine
DNA Replication
Codon
Escherichia coli
deoxyinosine
3,4-epoxy-1-butene
Protons
Hydrogen
Nucleotides
Cells

ASJC Scopus subject areas

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

Cite this

Dual roles of glycosyl torsion angle conformation and stereochemical configuration in butadiene oxide-derived N1 β-hydroxyalkyl deoxyinosine adducts : A structural perspective. / Merritt, W. Keither; Kowalczyk, Agnieszka; Scholdberg, Tandace A.; Dean, Stephen M.; Harris, Thomas M.; Harris, Constance M.; Lloyd, Robert (Stephen); Stone, Michael P.

In: Chemical Research in Toxicology, Vol. 18, No. 7, 07.2005, p. 1098-1107.

Research output: Contribution to journalArticle

Merritt, W. Keither ; Kowalczyk, Agnieszka ; Scholdberg, Tandace A. ; Dean, Stephen M. ; Harris, Thomas M. ; Harris, Constance M. ; Lloyd, Robert (Stephen) ; Stone, Michael P. / Dual roles of glycosyl torsion angle conformation and stereochemical configuration in butadiene oxide-derived N1 β-hydroxyalkyl deoxyinosine adducts : A structural perspective. In: Chemical Research in Toxicology. 2005 ; Vol. 18, No. 7. pp. 1098-1107.
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abstract = "The solution structure of the N1-[1-hydroxy-3-buten-2(R)-yl]-2′- deoxyinosine adduct arising from the alkylation of adenine N1 by butadiene epoxide (BDO), followed by deamination to deoxyinosine, was determined in the oligodeoxynucleotide 5′-d(CGGACXAGAAG)-3′-5′-d(CTTCTTGTCCG)- 3′. This oligodeoxynucleotide contained the BDO adduct at the second position of codon 61 of the human N-ras protooncogene (underlined) and was named the ras61 R-N1-BDO-(61,2) adduct. 1H NMR revealed a weak C 5 H1′ to X6 H8 nuclear Overhauser effects (NOE), followed by an intense X6 H8 to X6 H1′ NOE. Simultaneously, the X6 H8 to X6 H3′ NOE was weak. The resonances arising from the T16 and T17 imino protons were not observed. 1H NOEs between the butadiene moiety and the DNA positioned the adduct in the major groove. Structural refinement based upon a total of 394 NOE-derived distance restraints and 151 torsion angle restraints yielded a structure in which the modified deoxyinosine was in the syn conformation about the glycosyl bond, with a glycosyl bond angle of 83°, and T17, the complementary nucleotide, was stacked into the helix but not hydrogen bonded with the adducted inosine. The refined structure provides a plausible hypothesis as to why these N1 deoxyinosine adducts strongly code for the incorporation of dCTP during trans lesion DNA replication, irrespective of stereochemistry, both in Escherichia coli [Rodriguez, D. A., Kowalczyk, A., Ward, J. B. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2001) Environ. Mol. Mutagen. 38, 292-296] and in mammalian cells [Kanuri, M., Nechev, L. N., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572-1580]. Rotation of the N1 deoxyinosine adduct into the syn conformation may facilitate incorporation of dCTP via Hoogsteen type templating with deoxyinosine, generating A to G mutations. However, conformational differences between the R- and the S-N1-BDO-(61,2) adducts, involving the positioning of the butenyl moiety in the major groove of DNA, suggest that adduct stereochemistry plays a secondary role in modulating the biological response to these adducts.",
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T1 - Dual roles of glycosyl torsion angle conformation and stereochemical configuration in butadiene oxide-derived N1 β-hydroxyalkyl deoxyinosine adducts

T2 - A structural perspective

AU - Merritt, W. Keither

AU - Kowalczyk, Agnieszka

AU - Scholdberg, Tandace A.

AU - Dean, Stephen M.

AU - Harris, Thomas M.

AU - Harris, Constance M.

AU - Lloyd, Robert (Stephen)

AU - Stone, Michael P.

PY - 2005/7

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N2 - The solution structure of the N1-[1-hydroxy-3-buten-2(R)-yl]-2′- deoxyinosine adduct arising from the alkylation of adenine N1 by butadiene epoxide (BDO), followed by deamination to deoxyinosine, was determined in the oligodeoxynucleotide 5′-d(CGGACXAGAAG)-3′-5′-d(CTTCTTGTCCG)- 3′. This oligodeoxynucleotide contained the BDO adduct at the second position of codon 61 of the human N-ras protooncogene (underlined) and was named the ras61 R-N1-BDO-(61,2) adduct. 1H NMR revealed a weak C 5 H1′ to X6 H8 nuclear Overhauser effects (NOE), followed by an intense X6 H8 to X6 H1′ NOE. Simultaneously, the X6 H8 to X6 H3′ NOE was weak. The resonances arising from the T16 and T17 imino protons were not observed. 1H NOEs between the butadiene moiety and the DNA positioned the adduct in the major groove. Structural refinement based upon a total of 394 NOE-derived distance restraints and 151 torsion angle restraints yielded a structure in which the modified deoxyinosine was in the syn conformation about the glycosyl bond, with a glycosyl bond angle of 83°, and T17, the complementary nucleotide, was stacked into the helix but not hydrogen bonded with the adducted inosine. The refined structure provides a plausible hypothesis as to why these N1 deoxyinosine adducts strongly code for the incorporation of dCTP during trans lesion DNA replication, irrespective of stereochemistry, both in Escherichia coli [Rodriguez, D. A., Kowalczyk, A., Ward, J. B. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2001) Environ. Mol. Mutagen. 38, 292-296] and in mammalian cells [Kanuri, M., Nechev, L. N., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572-1580]. Rotation of the N1 deoxyinosine adduct into the syn conformation may facilitate incorporation of dCTP via Hoogsteen type templating with deoxyinosine, generating A to G mutations. However, conformational differences between the R- and the S-N1-BDO-(61,2) adducts, involving the positioning of the butenyl moiety in the major groove of DNA, suggest that adduct stereochemistry plays a secondary role in modulating the biological response to these adducts.

AB - The solution structure of the N1-[1-hydroxy-3-buten-2(R)-yl]-2′- deoxyinosine adduct arising from the alkylation of adenine N1 by butadiene epoxide (BDO), followed by deamination to deoxyinosine, was determined in the oligodeoxynucleotide 5′-d(CGGACXAGAAG)-3′-5′-d(CTTCTTGTCCG)- 3′. This oligodeoxynucleotide contained the BDO adduct at the second position of codon 61 of the human N-ras protooncogene (underlined) and was named the ras61 R-N1-BDO-(61,2) adduct. 1H NMR revealed a weak C 5 H1′ to X6 H8 nuclear Overhauser effects (NOE), followed by an intense X6 H8 to X6 H1′ NOE. Simultaneously, the X6 H8 to X6 H3′ NOE was weak. The resonances arising from the T16 and T17 imino protons were not observed. 1H NOEs between the butadiene moiety and the DNA positioned the adduct in the major groove. Structural refinement based upon a total of 394 NOE-derived distance restraints and 151 torsion angle restraints yielded a structure in which the modified deoxyinosine was in the syn conformation about the glycosyl bond, with a glycosyl bond angle of 83°, and T17, the complementary nucleotide, was stacked into the helix but not hydrogen bonded with the adducted inosine. The refined structure provides a plausible hypothesis as to why these N1 deoxyinosine adducts strongly code for the incorporation of dCTP during trans lesion DNA replication, irrespective of stereochemistry, both in Escherichia coli [Rodriguez, D. A., Kowalczyk, A., Ward, J. B. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2001) Environ. Mol. Mutagen. 38, 292-296] and in mammalian cells [Kanuri, M., Nechev, L. N., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572-1580]. Rotation of the N1 deoxyinosine adduct into the syn conformation may facilitate incorporation of dCTP via Hoogsteen type templating with deoxyinosine, generating A to G mutations. However, conformational differences between the R- and the S-N1-BDO-(61,2) adducts, involving the positioning of the butenyl moiety in the major groove of DNA, suggest that adduct stereochemistry plays a secondary role in modulating the biological response to these adducts.

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