Orientation of the crotonaldehyde-derived N2[3-oxo-1(S)-methyl- propyl]-dG DNA adduct hinders interstrand cross-link formation in the 5′-CpG-3′ sequence

Young Jin Cho, Hao Wang, Ivan D. Kozekov, Albena Kozekova, Andrew J. Kurtz, Jaison Jacob, Markus Voehler, Jarrod Smith, Thomas M. Harris, Carmelo J. Rizzo, Robert (Stephen) Lloyd, Michael P. Stone

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The conformation of the crotonaldehyde-derived N2-[3-oxo-1(S)- methyl-propyl]-dG adduct in the oligodeoxynucleotide 5′-d(G 1C2T3A4G5C 6X7A8G9T10C 11C12)-3′-5′-d(G13G 14A15C16T17C18G 19C20T21A22G23C 24)-3′, where X = N2-[3-oxo-1(S)-methyl-propyl]-dG, is reported. This adduct arises from opening of the cyclic N2-(S- α-CH3-γ-OH-1,N2-propano-2′)-dG adduct when placed opposite dC in duplex DNA. This oligodeoxynucleotide contains the 5′-CpG-3′ sequence in which the N2-(R-α-CH 3-γ-OH-1,N2-propano-2′)-dG but not the N 2-(S-α-CH3-γ-OH-1,N2-propano- 2′)-dG adduct preferentially formed an interstrand carbinolamine cross-link [Kozekov, I. D., Nechev, L. V., Moseley, M. S., Harris, C. M., Rizzo, C. J., Stone, M. P., and Harris, T. M. (2003) J. Am. Chem. Soc. 125, 50-61; Cho, Y.-J., Wang, H., Kozekov, I. D., Kurtz, A. J., Jacob, J., Voehler, M., Smith, J., Harris, T. M., Lloyd, R. S., Rizzo, C. J., and Stone, M. P. (2006) Chem. Res. Toxicol. 19, 195-208]. Analysis of 1H NOE data, chemical shift perturbations, and deoxyribose pseudorotations and backbone torsion angles suggested the presence of a stable and ordered DNA conformation at pH 9.3 and 30 °C, with minimal conformational perturbation. The spectral line widths of the adduct protons were comparable to those of the oligodeoxynucleotide, suggesting that the correlation times of these protons were similar to those of the overall duplex. The crotonaldehydic-derived methyl protons showed NOEs in the 5′-direction to C18 H1′, G19 H1′, and G19 H4′ in the complementary strand of the duplex. The aldehyde proton of the adduct exhibited NOEs in the 3′-direction to A 8 H1′ and A8 H4′ in the modified strand. All of these NOEs involved DNA protons facing the minor groove. Molecular dynamics calculations, restrained by distances and torsion angles derived from the NMR data, revealed that within the minor groove, the aldehyde of the N 2-[3-oxo-1(S)-methyl-propyl]-dG adduct oriented in the 3′-direction, while the 1(S) methyl group oriented in the 5′-direction. This positioned the aldehyde distal to the G19 exocyclic amine and provided a rationale as to why the N2-(S-α- CH3-γ-OH-1,N2-propano-2′)-dG adduct generated interstrand cross-links less efficiently than did the N2-(R-α- CH3-γ-OH-1,N2-propano-2′)-dG adduct.

Original languageEnglish (US)
Pages (from-to)1019-1029
Number of pages11
JournalChemical Research in Toxicology
Volume19
Issue number8
DOIs
StatePublished - Aug 2006

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2-butenal
DNA Adducts
Protons
Oligodeoxyribonucleotides
Aldehydes
Torsional stress
Conformations
DNA
Deoxyribose
Nucleic Acid Conformation
Chemical shift
Molecular Dynamics Simulation
Linewidth
Amines
Molecular dynamics
Nuclear magnetic resonance
hydroxide ion

ASJC Scopus subject areas

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

Cite this

Orientation of the crotonaldehyde-derived N2[3-oxo-1(S)-methyl- propyl]-dG DNA adduct hinders interstrand cross-link formation in the 5′-CpG-3′ sequence. / Cho, Young Jin; Wang, Hao; Kozekov, Ivan D.; Kozekova, Albena; Kurtz, Andrew J.; Jacob, Jaison; Voehler, Markus; Smith, Jarrod; Harris, Thomas M.; Rizzo, Carmelo J.; Lloyd, Robert (Stephen); Stone, Michael P.

In: Chemical Research in Toxicology, Vol. 19, No. 8, 08.2006, p. 1019-1029.

Research output: Contribution to journalArticle

Cho, YJ, Wang, H, Kozekov, ID, Kozekova, A, Kurtz, AJ, Jacob, J, Voehler, M, Smith, J, Harris, TM, Rizzo, CJ, Lloyd, RS & Stone, MP 2006, 'Orientation of the crotonaldehyde-derived N2[3-oxo-1(S)-methyl- propyl]-dG DNA adduct hinders interstrand cross-link formation in the 5′-CpG-3′ sequence', Chemical Research in Toxicology, vol. 19, no. 8, pp. 1019-1029. https://doi.org/10.1021/tx0600604
Cho, Young Jin ; Wang, Hao ; Kozekov, Ivan D. ; Kozekova, Albena ; Kurtz, Andrew J. ; Jacob, Jaison ; Voehler, Markus ; Smith, Jarrod ; Harris, Thomas M. ; Rizzo, Carmelo J. ; Lloyd, Robert (Stephen) ; Stone, Michael P. / Orientation of the crotonaldehyde-derived N2[3-oxo-1(S)-methyl- propyl]-dG DNA adduct hinders interstrand cross-link formation in the 5′-CpG-3′ sequence. In: Chemical Research in Toxicology. 2006 ; Vol. 19, No. 8. pp. 1019-1029.
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title = "Orientation of the crotonaldehyde-derived N2[3-oxo-1(S)-methyl- propyl]-dG DNA adduct hinders interstrand cross-link formation in the 5′-CpG-3′ sequence",
abstract = "The conformation of the crotonaldehyde-derived N2-[3-oxo-1(S)- methyl-propyl]-dG adduct in the oligodeoxynucleotide 5′-d(G 1C2T3A4G5C 6X7A8G9T10C 11C12)-3′-5′-d(G13G 14A15C16T17C18G 19C20T21A22G23C 24)-3′, where X = N2-[3-oxo-1(S)-methyl-propyl]-dG, is reported. This adduct arises from opening of the cyclic N2-(S- α-CH3-γ-OH-1,N2-propano-2′)-dG adduct when placed opposite dC in duplex DNA. This oligodeoxynucleotide contains the 5′-CpG-3′ sequence in which the N2-(R-α-CH 3-γ-OH-1,N2-propano-2′)-dG but not the N 2-(S-α-CH3-γ-OH-1,N2-propano- 2′)-dG adduct preferentially formed an interstrand carbinolamine cross-link [Kozekov, I. D., Nechev, L. V., Moseley, M. S., Harris, C. M., Rizzo, C. J., Stone, M. P., and Harris, T. M. (2003) J. Am. Chem. Soc. 125, 50-61; Cho, Y.-J., Wang, H., Kozekov, I. D., Kurtz, A. J., Jacob, J., Voehler, M., Smith, J., Harris, T. M., Lloyd, R. S., Rizzo, C. J., and Stone, M. P. (2006) Chem. Res. Toxicol. 19, 195-208]. Analysis of 1H NOE data, chemical shift perturbations, and deoxyribose pseudorotations and backbone torsion angles suggested the presence of a stable and ordered DNA conformation at pH 9.3 and 30 °C, with minimal conformational perturbation. The spectral line widths of the adduct protons were comparable to those of the oligodeoxynucleotide, suggesting that the correlation times of these protons were similar to those of the overall duplex. The crotonaldehydic-derived methyl protons showed NOEs in the 5′-direction to C18 H1′, G19 H1′, and G19 H4′ in the complementary strand of the duplex. The aldehyde proton of the adduct exhibited NOEs in the 3′-direction to A 8 H1′ and A8 H4′ in the modified strand. All of these NOEs involved DNA protons facing the minor groove. Molecular dynamics calculations, restrained by distances and torsion angles derived from the NMR data, revealed that within the minor groove, the aldehyde of the N 2-[3-oxo-1(S)-methyl-propyl]-dG adduct oriented in the 3′-direction, while the 1(S) methyl group oriented in the 5′-direction. This positioned the aldehyde distal to the G19 exocyclic amine and provided a rationale as to why the N2-(S-α- CH3-γ-OH-1,N2-propano-2′)-dG adduct generated interstrand cross-links less efficiently than did the N2-(R-α- CH3-γ-OH-1,N2-propano-2′)-dG adduct.",
author = "Cho, {Young Jin} and Hao Wang and Kozekov, {Ivan D.} and Albena Kozekova and Kurtz, {Andrew J.} and Jaison Jacob and Markus Voehler and Jarrod Smith and Harris, {Thomas M.} and Rizzo, {Carmelo J.} and Lloyd, {Robert (Stephen)} and Stone, {Michael P.}",
year = "2006",
month = "8",
doi = "10.1021/tx0600604",
language = "English (US)",
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pages = "1019--1029",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
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TY - JOUR

T1 - Orientation of the crotonaldehyde-derived N2[3-oxo-1(S)-methyl- propyl]-dG DNA adduct hinders interstrand cross-link formation in the 5′-CpG-3′ sequence

AU - Cho, Young Jin

AU - Wang, Hao

AU - Kozekov, Ivan D.

AU - Kozekova, Albena

AU - Kurtz, Andrew J.

AU - Jacob, Jaison

AU - Voehler, Markus

AU - Smith, Jarrod

AU - Harris, Thomas M.

AU - Rizzo, Carmelo J.

AU - Lloyd, Robert (Stephen)

AU - Stone, Michael P.

PY - 2006/8

Y1 - 2006/8

N2 - The conformation of the crotonaldehyde-derived N2-[3-oxo-1(S)- methyl-propyl]-dG adduct in the oligodeoxynucleotide 5′-d(G 1C2T3A4G5C 6X7A8G9T10C 11C12)-3′-5′-d(G13G 14A15C16T17C18G 19C20T21A22G23C 24)-3′, where X = N2-[3-oxo-1(S)-methyl-propyl]-dG, is reported. This adduct arises from opening of the cyclic N2-(S- α-CH3-γ-OH-1,N2-propano-2′)-dG adduct when placed opposite dC in duplex DNA. This oligodeoxynucleotide contains the 5′-CpG-3′ sequence in which the N2-(R-α-CH 3-γ-OH-1,N2-propano-2′)-dG but not the N 2-(S-α-CH3-γ-OH-1,N2-propano- 2′)-dG adduct preferentially formed an interstrand carbinolamine cross-link [Kozekov, I. D., Nechev, L. V., Moseley, M. S., Harris, C. M., Rizzo, C. J., Stone, M. P., and Harris, T. M. (2003) J. Am. Chem. Soc. 125, 50-61; Cho, Y.-J., Wang, H., Kozekov, I. D., Kurtz, A. J., Jacob, J., Voehler, M., Smith, J., Harris, T. M., Lloyd, R. S., Rizzo, C. J., and Stone, M. P. (2006) Chem. Res. Toxicol. 19, 195-208]. Analysis of 1H NOE data, chemical shift perturbations, and deoxyribose pseudorotations and backbone torsion angles suggested the presence of a stable and ordered DNA conformation at pH 9.3 and 30 °C, with minimal conformational perturbation. The spectral line widths of the adduct protons were comparable to those of the oligodeoxynucleotide, suggesting that the correlation times of these protons were similar to those of the overall duplex. The crotonaldehydic-derived methyl protons showed NOEs in the 5′-direction to C18 H1′, G19 H1′, and G19 H4′ in the complementary strand of the duplex. The aldehyde proton of the adduct exhibited NOEs in the 3′-direction to A 8 H1′ and A8 H4′ in the modified strand. All of these NOEs involved DNA protons facing the minor groove. Molecular dynamics calculations, restrained by distances and torsion angles derived from the NMR data, revealed that within the minor groove, the aldehyde of the N 2-[3-oxo-1(S)-methyl-propyl]-dG adduct oriented in the 3′-direction, while the 1(S) methyl group oriented in the 5′-direction. This positioned the aldehyde distal to the G19 exocyclic amine and provided a rationale as to why the N2-(S-α- CH3-γ-OH-1,N2-propano-2′)-dG adduct generated interstrand cross-links less efficiently than did the N2-(R-α- CH3-γ-OH-1,N2-propano-2′)-dG adduct.

AB - The conformation of the crotonaldehyde-derived N2-[3-oxo-1(S)- methyl-propyl]-dG adduct in the oligodeoxynucleotide 5′-d(G 1C2T3A4G5C 6X7A8G9T10C 11C12)-3′-5′-d(G13G 14A15C16T17C18G 19C20T21A22G23C 24)-3′, where X = N2-[3-oxo-1(S)-methyl-propyl]-dG, is reported. This adduct arises from opening of the cyclic N2-(S- α-CH3-γ-OH-1,N2-propano-2′)-dG adduct when placed opposite dC in duplex DNA. This oligodeoxynucleotide contains the 5′-CpG-3′ sequence in which the N2-(R-α-CH 3-γ-OH-1,N2-propano-2′)-dG but not the N 2-(S-α-CH3-γ-OH-1,N2-propano- 2′)-dG adduct preferentially formed an interstrand carbinolamine cross-link [Kozekov, I. D., Nechev, L. V., Moseley, M. S., Harris, C. M., Rizzo, C. J., Stone, M. P., and Harris, T. M. (2003) J. Am. Chem. Soc. 125, 50-61; Cho, Y.-J., Wang, H., Kozekov, I. D., Kurtz, A. J., Jacob, J., Voehler, M., Smith, J., Harris, T. M., Lloyd, R. S., Rizzo, C. J., and Stone, M. P. (2006) Chem. Res. Toxicol. 19, 195-208]. Analysis of 1H NOE data, chemical shift perturbations, and deoxyribose pseudorotations and backbone torsion angles suggested the presence of a stable and ordered DNA conformation at pH 9.3 and 30 °C, with minimal conformational perturbation. The spectral line widths of the adduct protons were comparable to those of the oligodeoxynucleotide, suggesting that the correlation times of these protons were similar to those of the overall duplex. The crotonaldehydic-derived methyl protons showed NOEs in the 5′-direction to C18 H1′, G19 H1′, and G19 H4′ in the complementary strand of the duplex. The aldehyde proton of the adduct exhibited NOEs in the 3′-direction to A 8 H1′ and A8 H4′ in the modified strand. All of these NOEs involved DNA protons facing the minor groove. Molecular dynamics calculations, restrained by distances and torsion angles derived from the NMR data, revealed that within the minor groove, the aldehyde of the N 2-[3-oxo-1(S)-methyl-propyl]-dG adduct oriented in the 3′-direction, while the 1(S) methyl group oriented in the 5′-direction. This positioned the aldehyde distal to the G19 exocyclic amine and provided a rationale as to why the N2-(S-α- CH3-γ-OH-1,N2-propano-2′)-dG adduct generated interstrand cross-links less efficiently than did the N2-(R-α- CH3-γ-OH-1,N2-propano-2′)-dG adduct.

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