NMR solution structures of stereoisomeric covalent polycyclic aromatic carcinogen-DNA adducts: Principles, patterns, and diversity

Nicholas E. Geacintov, Monique Cosman, Brian E. Hingerty, Shantu Amin, Suse Broyde, Dinshaw J. Patel

Research output: Contribution to journalArticle

Abstract

The NMR structural studies have elucidated a variety of strikingly diverse conformational themes among adducts of polycyclic aromatic compounds with DNA. Three basic types of conformers have been discovered for PAH-DNA adducts (Table 4, Figures 11, 12, and 18): (1) minor groove external binding sites, (2) base-displaced intercalative structures, and (3) intercalative insertions of the bulky PAH residues into the helix without base displacement (modified classical intercalation). An additional conformational motif, a major groove adduct structure in the case of α-(N6-adenyl)styrene oxide adducts, has been observed (Table 4). The opposite orientations relative to the modified bases of chemically identical adduct pairs derived from chiral pairs of diol epoxide stereoisomers are noteworthy. Remarkably, this theme of opposite orientations persists regardless of (1) the conformer type (minor groove, base-displaced/intercalation, classical intercalation), or (2) the nature of the polycyclic aromatic parent compound (5-MeC, BPh, BP, α-[SO]) and adduct site (guanine or adenine group, see Table 4). The conformational theme of base-displaced intercalation, observed in the cases of the cis- anti-[BP]N2-dG adducts, is also found for adducts derived from polycyclic aromatic amines. The possibility that the minor groove and base-displaced intercalated [BP]-N2-dG adducts may exist in equilibrium with one another is proposed, and the structural basis and experimental evidence for such equilibria are discussed in detail. In the aromatic amine series, base- displaced/intercalation structures have been observed for N-acetyl-2- aminofluorene (39), 2-aminofluorene (40-42, 44, 45), and 1-aminopyrene (46), and an equilibrium between such states was also observed in the 2- aminofluorene case (40-42). An equilibrium is also indicated in the solution structure of a 4-aminobiphenyl adduct (43). We hypothesize that such equilibria may prevail in other adducts derived from polycyclic aromatic hydrocarbons and amines, as well. The concept of an equilibrium between inserted and external conformers had also been foreshadowed in early computations and was coupled with the suggestion that inserted conformers might be mutagenic (163-165), an idea that has since been advanced also by Eckel and Krugh (41, 42) on the basis of their experimental work on 2- aminofluorene. A number of critical objectives and important issues remain to be addressed. Among these are the effects of base sequence context on adduct conformations. Several existing results point to the importance of the flanking bases on adduct conformations, and this issue needs to be explored in greater detail. The effects of flanking bases on the types of structural deformations caused by PAH lesions at single strand-double strand junctions, relevant to biochemical events during replication, appear to be particularly important for gaining insight into the molecular events underlying hotspot phenomena in mutagenesis. Ultimately, the complex problem of the role of the protein or enzyme environment in PAH-DNA adduct conformation and function will need to be addressed. There is no doubt that this issue is one of the most important goals for achieving a better understanding of structure- biological function relationships.

Original languageEnglish (US)
Pages (from-to)111-146
Number of pages36
JournalChemical Research in Toxicology
Volume10
Issue number2
DOIs
StatePublished - Feb 1997

Fingerprint

DNA Adducts
Intercalation
Carcinogens
Amines
styrene oxide
Nuclear magnetic resonance
Conformations
Polycyclic Compounds
Aromatic compounds
Nucleic Acid Conformation
2-Acetylaminofluorene
Polycyclic aromatic hydrocarbons
Stereoisomerism
Polycyclic Aromatic Hydrocarbons
Epoxy Compounds
Guanine
Adenine
Mutagenesis
Binding Sites
DNA

ASJC Scopus subject areas

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

Cite this

NMR solution structures of stereoisomeric covalent polycyclic aromatic carcinogen-DNA adducts : Principles, patterns, and diversity. / Geacintov, Nicholas E.; Cosman, Monique; Hingerty, Brian E.; Amin, Shantu; Broyde, Suse; Patel, Dinshaw J.

In: Chemical Research in Toxicology, Vol. 10, No. 2, 02.1997, p. 111-146.

Research output: Contribution to journalArticle

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abstract = "The NMR structural studies have elucidated a variety of strikingly diverse conformational themes among adducts of polycyclic aromatic compounds with DNA. Three basic types of conformers have been discovered for PAH-DNA adducts (Table 4, Figures 11, 12, and 18): (1) minor groove external binding sites, (2) base-displaced intercalative structures, and (3) intercalative insertions of the bulky PAH residues into the helix without base displacement (modified classical intercalation). An additional conformational motif, a major groove adduct structure in the case of α-(N6-adenyl)styrene oxide adducts, has been observed (Table 4). The opposite orientations relative to the modified bases of chemically identical adduct pairs derived from chiral pairs of diol epoxide stereoisomers are noteworthy. Remarkably, this theme of opposite orientations persists regardless of (1) the conformer type (minor groove, base-displaced/intercalation, classical intercalation), or (2) the nature of the polycyclic aromatic parent compound (5-MeC, BPh, BP, α-[SO]) and adduct site (guanine or adenine group, see Table 4). The conformational theme of base-displaced intercalation, observed in the cases of the cis- anti-[BP]N2-dG adducts, is also found for adducts derived from polycyclic aromatic amines. The possibility that the minor groove and base-displaced intercalated [BP]-N2-dG adducts may exist in equilibrium with one another is proposed, and the structural basis and experimental evidence for such equilibria are discussed in detail. In the aromatic amine series, base- displaced/intercalation structures have been observed for N-acetyl-2- aminofluorene (39), 2-aminofluorene (40-42, 44, 45), and 1-aminopyrene (46), and an equilibrium between such states was also observed in the 2- aminofluorene case (40-42). An equilibrium is also indicated in the solution structure of a 4-aminobiphenyl adduct (43). We hypothesize that such equilibria may prevail in other adducts derived from polycyclic aromatic hydrocarbons and amines, as well. The concept of an equilibrium between inserted and external conformers had also been foreshadowed in early computations and was coupled with the suggestion that inserted conformers might be mutagenic (163-165), an idea that has since been advanced also by Eckel and Krugh (41, 42) on the basis of their experimental work on 2- aminofluorene. A number of critical objectives and important issues remain to be addressed. Among these are the effects of base sequence context on adduct conformations. Several existing results point to the importance of the flanking bases on adduct conformations, and this issue needs to be explored in greater detail. The effects of flanking bases on the types of structural deformations caused by PAH lesions at single strand-double strand junctions, relevant to biochemical events during replication, appear to be particularly important for gaining insight into the molecular events underlying hotspot phenomena in mutagenesis. Ultimately, the complex problem of the role of the protein or enzyme environment in PAH-DNA adduct conformation and function will need to be addressed. There is no doubt that this issue is one of the most important goals for achieving a better understanding of structure- biological function relationships.",
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T1 - NMR solution structures of stereoisomeric covalent polycyclic aromatic carcinogen-DNA adducts

T2 - Principles, patterns, and diversity

AU - Geacintov, Nicholas E.

AU - Cosman, Monique

AU - Hingerty, Brian E.

AU - Amin, Shantu

AU - Broyde, Suse

AU - Patel, Dinshaw J.

PY - 1997/2

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N2 - The NMR structural studies have elucidated a variety of strikingly diverse conformational themes among adducts of polycyclic aromatic compounds with DNA. Three basic types of conformers have been discovered for PAH-DNA adducts (Table 4, Figures 11, 12, and 18): (1) minor groove external binding sites, (2) base-displaced intercalative structures, and (3) intercalative insertions of the bulky PAH residues into the helix without base displacement (modified classical intercalation). An additional conformational motif, a major groove adduct structure in the case of α-(N6-adenyl)styrene oxide adducts, has been observed (Table 4). The opposite orientations relative to the modified bases of chemically identical adduct pairs derived from chiral pairs of diol epoxide stereoisomers are noteworthy. Remarkably, this theme of opposite orientations persists regardless of (1) the conformer type (minor groove, base-displaced/intercalation, classical intercalation), or (2) the nature of the polycyclic aromatic parent compound (5-MeC, BPh, BP, α-[SO]) and adduct site (guanine or adenine group, see Table 4). The conformational theme of base-displaced intercalation, observed in the cases of the cis- anti-[BP]N2-dG adducts, is also found for adducts derived from polycyclic aromatic amines. The possibility that the minor groove and base-displaced intercalated [BP]-N2-dG adducts may exist in equilibrium with one another is proposed, and the structural basis and experimental evidence for such equilibria are discussed in detail. In the aromatic amine series, base- displaced/intercalation structures have been observed for N-acetyl-2- aminofluorene (39), 2-aminofluorene (40-42, 44, 45), and 1-aminopyrene (46), and an equilibrium between such states was also observed in the 2- aminofluorene case (40-42). An equilibrium is also indicated in the solution structure of a 4-aminobiphenyl adduct (43). We hypothesize that such equilibria may prevail in other adducts derived from polycyclic aromatic hydrocarbons and amines, as well. The concept of an equilibrium between inserted and external conformers had also been foreshadowed in early computations and was coupled with the suggestion that inserted conformers might be mutagenic (163-165), an idea that has since been advanced also by Eckel and Krugh (41, 42) on the basis of their experimental work on 2- aminofluorene. A number of critical objectives and important issues remain to be addressed. Among these are the effects of base sequence context on adduct conformations. Several existing results point to the importance of the flanking bases on adduct conformations, and this issue needs to be explored in greater detail. The effects of flanking bases on the types of structural deformations caused by PAH lesions at single strand-double strand junctions, relevant to biochemical events during replication, appear to be particularly important for gaining insight into the molecular events underlying hotspot phenomena in mutagenesis. Ultimately, the complex problem of the role of the protein or enzyme environment in PAH-DNA adduct conformation and function will need to be addressed. There is no doubt that this issue is one of the most important goals for achieving a better understanding of structure- biological function relationships.

AB - The NMR structural studies have elucidated a variety of strikingly diverse conformational themes among adducts of polycyclic aromatic compounds with DNA. Three basic types of conformers have been discovered for PAH-DNA adducts (Table 4, Figures 11, 12, and 18): (1) minor groove external binding sites, (2) base-displaced intercalative structures, and (3) intercalative insertions of the bulky PAH residues into the helix without base displacement (modified classical intercalation). An additional conformational motif, a major groove adduct structure in the case of α-(N6-adenyl)styrene oxide adducts, has been observed (Table 4). The opposite orientations relative to the modified bases of chemically identical adduct pairs derived from chiral pairs of diol epoxide stereoisomers are noteworthy. Remarkably, this theme of opposite orientations persists regardless of (1) the conformer type (minor groove, base-displaced/intercalation, classical intercalation), or (2) the nature of the polycyclic aromatic parent compound (5-MeC, BPh, BP, α-[SO]) and adduct site (guanine or adenine group, see Table 4). The conformational theme of base-displaced intercalation, observed in the cases of the cis- anti-[BP]N2-dG adducts, is also found for adducts derived from polycyclic aromatic amines. The possibility that the minor groove and base-displaced intercalated [BP]-N2-dG adducts may exist in equilibrium with one another is proposed, and the structural basis and experimental evidence for such equilibria are discussed in detail. In the aromatic amine series, base- displaced/intercalation structures have been observed for N-acetyl-2- aminofluorene (39), 2-aminofluorene (40-42, 44, 45), and 1-aminopyrene (46), and an equilibrium between such states was also observed in the 2- aminofluorene case (40-42). An equilibrium is also indicated in the solution structure of a 4-aminobiphenyl adduct (43). We hypothesize that such equilibria may prevail in other adducts derived from polycyclic aromatic hydrocarbons and amines, as well. The concept of an equilibrium between inserted and external conformers had also been foreshadowed in early computations and was coupled with the suggestion that inserted conformers might be mutagenic (163-165), an idea that has since been advanced also by Eckel and Krugh (41, 42) on the basis of their experimental work on 2- aminofluorene. A number of critical objectives and important issues remain to be addressed. Among these are the effects of base sequence context on adduct conformations. Several existing results point to the importance of the flanking bases on adduct conformations, and this issue needs to be explored in greater detail. The effects of flanking bases on the types of structural deformations caused by PAH lesions at single strand-double strand junctions, relevant to biochemical events during replication, appear to be particularly important for gaining insight into the molecular events underlying hotspot phenomena in mutagenesis. Ultimately, the complex problem of the role of the protein or enzyme environment in PAH-DNA adduct conformation and function will need to be addressed. There is no doubt that this issue is one of the most important goals for achieving a better understanding of structure- biological function relationships.

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