Stereospecific structural perturbations arising from adenine N6 butadiene triol adducts in duplex DNA

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

Research output: Contribution to journalArticle

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Abstract

Butadiene is oxidized in vivo to form stereoisomeric butadiene diol epoxides (BDE). These react with adenine N6 in DNA yielding stereoisomeric N6-(2,3,4-trihydroxybutyl)-2′-deoxyadenosyl (BDT) adducts. When replicated in Escherichia coli, the (2R,3J)-N 6-(2,3,4-trihydroxybutyl)-2′-deoxyadenosyl adduct yielded low levels of A→G mutations whereas the (2S,3S)-N6-(2,3,4- trihydroxybutyl)-2′-deoxyadenosyl butadiene triol adduct yielded low levels of A→C mutations [Carmical, J. R., Nechev, L. V., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Environ. Mol. Mutagen. 35, 48-56]. Accordingly, the structure of the (2R,3R)-N6-(2,3,4-trihydroxybutyl)- 2′-deoxyadenosyl adduct at position X6 in d(CGGACXAGAAG) ·d(CTTCTTGTCCG), the ras61 R,R-BDT-(61,2) adduct, was compared to the corresponding structure for the (2S,3S)-N6-(2,3,4-trihydroxybutyl)- 2′-deoxyadenosyl adduct in the same sequence, the ras61 S,S-BDT-(61,2) adduct. Both the R,R-BDT-(61,2) and S,S-BDT-(61,2) adducts are oriented in the major groove of the DNA, accompanied by modest structural perturbations. However, structural refinement of the two adducts using a simulated annealing restrained molecular dynamics (rMD) approach suggests stereospecific differences in hydrogen bonding between the hydroxyl groups located at the β- and γ-carbons of the BDT moiety, and T17 O4 of the modified base pair X6·T17. The rMD calculations predict hydrogen bond formation between the β-OH and the T17 O4in the R,R-BDT-(61,2) adduct whereas in the S,S-BDT-(61,2) adduct, hydrogen bond formation is predicted between the β-OH and the T 17 O4. This difference positions the two adducts differently in the major groove. This may account for the differential mutagenicity of the two adducts and suggests that the two adducts may interact differentially with other DNA processing enzymes. With respect to mutagenesis in E. coli, the minimal perturbation of DNA induced by both major groove adducts correlates with their facile bypass by three E. coli DNA polymerases in vitro and may account for their weak mutagenicity [Carmical, J. R., Nechev, L. V., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Environ. Mol. Mutasen. 35. 48-56].

Original languageEnglish (US)
Pages (from-to)1007-1019
Number of pages13
JournalChemical Research in Toxicology
Volume17
Issue number8
DOIs
StatePublished - Aug 2004

Fingerprint

Adenine
DNA
Escherichia coli
Hydrogen bonds
Molecular Dynamics Simulation
Molecular dynamics
Hydrogen
Mutagenesis
Mutation
1,3-butadiene
N-((2,3-dihydro-1,4-benzodioxin-2-yl)methyl)-5-methoxy-1H-indole-3-ethanamine
Epoxy Compounds
Mutagens
DNA-Directed DNA Polymerase
Hydrogen Bonding
Simulated annealing
Base Pairing
Hydroxyl Radical
Carbon
Enzymes

ASJC Scopus subject areas

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

Cite this

Merritt, W. K., Scholdberg, T. A., Nechev, L. V., Harris, T. M., Harris, C. M., Lloyd, R. S., & Stone, M. P. (2004). Stereospecific structural perturbations arising from adenine N6 butadiene triol adducts in duplex DNA. Chemical Research in Toxicology, 17(8), 1007-1019. https://doi.org/10.1021/tx049908j

Stereospecific structural perturbations arising from adenine N6 butadiene triol adducts in duplex DNA. / Merritt, W. Keither; Scholdberg, Tandace A.; Nechev, Lubomir V.; Harris, Thomas M.; Harris, Constance M.; Lloyd, Robert (Stephen); Stone, Michael P.

In: Chemical Research in Toxicology, Vol. 17, No. 8, 08.2004, p. 1007-1019.

Research output: Contribution to journalArticle

Merritt, WK, Scholdberg, TA, Nechev, LV, Harris, TM, Harris, CM, Lloyd, RS & Stone, MP 2004, 'Stereospecific structural perturbations arising from adenine N6 butadiene triol adducts in duplex DNA', Chemical Research in Toxicology, vol. 17, no. 8, pp. 1007-1019. https://doi.org/10.1021/tx049908j
Merritt, W. Keither ; Scholdberg, Tandace A. ; Nechev, Lubomir V. ; Harris, Thomas M. ; Harris, Constance M. ; Lloyd, Robert (Stephen) ; Stone, Michael P. / Stereospecific structural perturbations arising from adenine N6 butadiene triol adducts in duplex DNA. In: Chemical Research in Toxicology. 2004 ; Vol. 17, No. 8. pp. 1007-1019.
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abstract = "Butadiene is oxidized in vivo to form stereoisomeric butadiene diol epoxides (BDE). These react with adenine N6 in DNA yielding stereoisomeric N6-(2,3,4-trihydroxybutyl)-2′-deoxyadenosyl (BDT) adducts. When replicated in Escherichia coli, the (2R,3J)-N 6-(2,3,4-trihydroxybutyl)-2′-deoxyadenosyl adduct yielded low levels of A→G mutations whereas the (2S,3S)-N6-(2,3,4- trihydroxybutyl)-2′-deoxyadenosyl butadiene triol adduct yielded low levels of A→C mutations [Carmical, J. R., Nechev, L. V., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Environ. Mol. Mutagen. 35, 48-56]. Accordingly, the structure of the (2R,3R)-N6-(2,3,4-trihydroxybutyl)- 2′-deoxyadenosyl adduct at position X6 in d(CGGACXAGAAG) ·d(CTTCTTGTCCG), the ras61 R,R-BDT-(61,2) adduct, was compared to the corresponding structure for the (2S,3S)-N6-(2,3,4-trihydroxybutyl)- 2′-deoxyadenosyl adduct in the same sequence, the ras61 S,S-BDT-(61,2) adduct. Both the R,R-BDT-(61,2) and S,S-BDT-(61,2) adducts are oriented in the major groove of the DNA, accompanied by modest structural perturbations. However, structural refinement of the two adducts using a simulated annealing restrained molecular dynamics (rMD) approach suggests stereospecific differences in hydrogen bonding between the hydroxyl groups located at the β- and γ-carbons of the BDT moiety, and T17 O4 of the modified base pair X6·T17. The rMD calculations predict hydrogen bond formation between the β-OH and the T17 O4in the R,R-BDT-(61,2) adduct whereas in the S,S-BDT-(61,2) adduct, hydrogen bond formation is predicted between the β-OH and the T 17 O4. This difference positions the two adducts differently in the major groove. This may account for the differential mutagenicity of the two adducts and suggests that the two adducts may interact differentially with other DNA processing enzymes. With respect to mutagenesis in E. coli, the minimal perturbation of DNA induced by both major groove adducts correlates with their facile bypass by three E. coli DNA polymerases in vitro and may account for their weak mutagenicity [Carmical, J. R., Nechev, L. V., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Environ. Mol. Mutasen. 35. 48-56].",
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T1 - Stereospecific structural perturbations arising from adenine N6 butadiene triol adducts in duplex DNA

AU - Merritt, W. Keither

AU - Scholdberg, Tandace A.

AU - Nechev, Lubomir V.

AU - Harris, Thomas M.

AU - Harris, Constance M.

AU - Lloyd, Robert (Stephen)

AU - Stone, Michael P.

PY - 2004/8

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N2 - Butadiene is oxidized in vivo to form stereoisomeric butadiene diol epoxides (BDE). These react with adenine N6 in DNA yielding stereoisomeric N6-(2,3,4-trihydroxybutyl)-2′-deoxyadenosyl (BDT) adducts. When replicated in Escherichia coli, the (2R,3J)-N 6-(2,3,4-trihydroxybutyl)-2′-deoxyadenosyl adduct yielded low levels of A→G mutations whereas the (2S,3S)-N6-(2,3,4- trihydroxybutyl)-2′-deoxyadenosyl butadiene triol adduct yielded low levels of A→C mutations [Carmical, J. R., Nechev, L. V., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Environ. Mol. Mutagen. 35, 48-56]. Accordingly, the structure of the (2R,3R)-N6-(2,3,4-trihydroxybutyl)- 2′-deoxyadenosyl adduct at position X6 in d(CGGACXAGAAG) ·d(CTTCTTGTCCG), the ras61 R,R-BDT-(61,2) adduct, was compared to the corresponding structure for the (2S,3S)-N6-(2,3,4-trihydroxybutyl)- 2′-deoxyadenosyl adduct in the same sequence, the ras61 S,S-BDT-(61,2) adduct. Both the R,R-BDT-(61,2) and S,S-BDT-(61,2) adducts are oriented in the major groove of the DNA, accompanied by modest structural perturbations. However, structural refinement of the two adducts using a simulated annealing restrained molecular dynamics (rMD) approach suggests stereospecific differences in hydrogen bonding between the hydroxyl groups located at the β- and γ-carbons of the BDT moiety, and T17 O4 of the modified base pair X6·T17. The rMD calculations predict hydrogen bond formation between the β-OH and the T17 O4in the R,R-BDT-(61,2) adduct whereas in the S,S-BDT-(61,2) adduct, hydrogen bond formation is predicted between the β-OH and the T 17 O4. This difference positions the two adducts differently in the major groove. This may account for the differential mutagenicity of the two adducts and suggests that the two adducts may interact differentially with other DNA processing enzymes. With respect to mutagenesis in E. coli, the minimal perturbation of DNA induced by both major groove adducts correlates with their facile bypass by three E. coli DNA polymerases in vitro and may account for their weak mutagenicity [Carmical, J. R., Nechev, L. V., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Environ. Mol. Mutasen. 35. 48-56].

AB - Butadiene is oxidized in vivo to form stereoisomeric butadiene diol epoxides (BDE). These react with adenine N6 in DNA yielding stereoisomeric N6-(2,3,4-trihydroxybutyl)-2′-deoxyadenosyl (BDT) adducts. When replicated in Escherichia coli, the (2R,3J)-N 6-(2,3,4-trihydroxybutyl)-2′-deoxyadenosyl adduct yielded low levels of A→G mutations whereas the (2S,3S)-N6-(2,3,4- trihydroxybutyl)-2′-deoxyadenosyl butadiene triol adduct yielded low levels of A→C mutations [Carmical, J. R., Nechev, L. V., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Environ. Mol. Mutagen. 35, 48-56]. Accordingly, the structure of the (2R,3R)-N6-(2,3,4-trihydroxybutyl)- 2′-deoxyadenosyl adduct at position X6 in d(CGGACXAGAAG) ·d(CTTCTTGTCCG), the ras61 R,R-BDT-(61,2) adduct, was compared to the corresponding structure for the (2S,3S)-N6-(2,3,4-trihydroxybutyl)- 2′-deoxyadenosyl adduct in the same sequence, the ras61 S,S-BDT-(61,2) adduct. Both the R,R-BDT-(61,2) and S,S-BDT-(61,2) adducts are oriented in the major groove of the DNA, accompanied by modest structural perturbations. However, structural refinement of the two adducts using a simulated annealing restrained molecular dynamics (rMD) approach suggests stereospecific differences in hydrogen bonding between the hydroxyl groups located at the β- and γ-carbons of the BDT moiety, and T17 O4 of the modified base pair X6·T17. The rMD calculations predict hydrogen bond formation between the β-OH and the T17 O4in the R,R-BDT-(61,2) adduct whereas in the S,S-BDT-(61,2) adduct, hydrogen bond formation is predicted between the β-OH and the T 17 O4. This difference positions the two adducts differently in the major groove. This may account for the differential mutagenicity of the two adducts and suggests that the two adducts may interact differentially with other DNA processing enzymes. With respect to mutagenesis in E. coli, the minimal perturbation of DNA induced by both major groove adducts correlates with their facile bypass by three E. coli DNA polymerases in vitro and may account for their weak mutagenicity [Carmical, J. R., Nechev, L. V., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Environ. Mol. Mutasen. 35. 48-56].

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