Structural and Stereoisomer Effects of Model Estrogen Quinone-Derived DNA Adducts: N6-(2-Hydroxyestron-6(α,β)-yl)-2′ -deoxyadenosine and N2-(2-Hydroxyestron-6(α,β )-yl)-2′-deoxyguanosine

Lihua Wang, Brian E. Hingerty, Robert Shapiro, Suse Broyde

Research output: Contribution to journalArticle

Abstract

An extensive conformational analysis has been carried out for two diastereoisomeric pairs of model estrogen quinone-derived DNA adducts, N 6-(2-hydroxyestron-6(α,β)-yl)-2′-deoxyadenosine (2-OHE1-6(α,β)-N6-dA) and N 2-(2-hydroxyestron-6(α,β)-yl)-2′-deoxyguanosine (2-OHE1-6(α,β)-N2-dG), in a B-DNA duplex and at a primer-template junction in a pol α family DNA polymerase. In vitro primer extension studies in pol α [Terashima, I., et al. (1998) Biochemistry 37, 13807-13815] have shown that the adenine adducts can incorporate dT, together with a small proportion of the incorrect base dC opposite the lesion, and they block less strongly than the guanine adducts. We have carried out conformational searches with energy minimization for four DNA duplexes containing 2-OHE1-6α-N6-dA, 2-OHE 1-6β-N6-dA, 2-OHE1-6α-N 2-dG, or 2-OHE1-6β-N2-dG. Our searches revealed that the four-ring nonplanar 2-hydroxyestrone (2-OHE1) moiety strongly prefers to reside in the major groove of the adenine adducts or the minor groove of the guanine adducts in a B-DNA duplex, with stereochemistry-dependent orientational differences in each case. No low energy conformations involving intercalation of the 2-OHE1 moiety were located in the searches. This stems from the largely nonplanar, nonaromatic nature of the 2-OHE1 ring system and implies that the proclivity for such bulky, nonplanar adducts to reside at the DNA helix exterior is a plausible conformational feature of other structurally similar estrogen quinone-derived DNA adducts, independent of base sequence context. In addition, the adenine adduct isomers, located in the major groove, manifest serious disturbance to the Watson-Crick base pairs at and near the lesion site, suggesting repair susceptibility. Possible structures of these adducts in a pol α family polymerase were also investigated through molecular modeling. The results rationalized the experimental in vitro primer extension studies. In addition, poor accommodation of the β-stereoisomers within the polymerase was noted, suggesting that these stereoisomers would be more prone to cause blockage. Stereochemistry-dependent differences in adduct orientation could be expected to produce different biochemical effects, as has been observed in adducts derived from polycyclic aromatic hydrocarbons.

Original languageEnglish (US)
Pages (from-to)311-324
Number of pages14
JournalChemical Research in Toxicology
Volume17
Issue number3
DOIs
StatePublished - Mar 2004

Fingerprint

Deoxyguanosine
Stereoisomerism
DNA Adducts
Adenine
B-Form DNA
Estrogens
Stereochemistry
Guanine
Biochemistry
Molecular modeling
DNA
Polycyclic Aromatic Hydrocarbons
DNA-Directed DNA Polymerase
Intercalation
Base Pairing
Isomers
Conformations
Repair
benzoquinone
2'-deoxyadenosine

ASJC Scopus subject areas

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

Cite this

@article{11bca236de32404eb154f3c713867510,
title = "Structural and Stereoisomer Effects of Model Estrogen Quinone-Derived DNA Adducts: N6-(2-Hydroxyestron-6(α,β)-yl)-2′ -deoxyadenosine and N2-(2-Hydroxyestron-6(α,β )-yl)-2′-deoxyguanosine",
abstract = "An extensive conformational analysis has been carried out for two diastereoisomeric pairs of model estrogen quinone-derived DNA adducts, N 6-(2-hydroxyestron-6(α,β)-yl)-2′-deoxyadenosine (2-OHE1-6(α,β)-N6-dA) and N 2-(2-hydroxyestron-6(α,β)-yl)-2′-deoxyguanosine (2-OHE1-6(α,β)-N2-dG), in a B-DNA duplex and at a primer-template junction in a pol α family DNA polymerase. In vitro primer extension studies in pol α [Terashima, I., et al. (1998) Biochemistry 37, 13807-13815] have shown that the adenine adducts can incorporate dT, together with a small proportion of the incorrect base dC opposite the lesion, and they block less strongly than the guanine adducts. We have carried out conformational searches with energy minimization for four DNA duplexes containing 2-OHE1-6α-N6-dA, 2-OHE 1-6β-N6-dA, 2-OHE1-6α-N 2-dG, or 2-OHE1-6β-N2-dG. Our searches revealed that the four-ring nonplanar 2-hydroxyestrone (2-OHE1) moiety strongly prefers to reside in the major groove of the adenine adducts or the minor groove of the guanine adducts in a B-DNA duplex, with stereochemistry-dependent orientational differences in each case. No low energy conformations involving intercalation of the 2-OHE1 moiety were located in the searches. This stems from the largely nonplanar, nonaromatic nature of the 2-OHE1 ring system and implies that the proclivity for such bulky, nonplanar adducts to reside at the DNA helix exterior is a plausible conformational feature of other structurally similar estrogen quinone-derived DNA adducts, independent of base sequence context. In addition, the adenine adduct isomers, located in the major groove, manifest serious disturbance to the Watson-Crick base pairs at and near the lesion site, suggesting repair susceptibility. Possible structures of these adducts in a pol α family polymerase were also investigated through molecular modeling. The results rationalized the experimental in vitro primer extension studies. In addition, poor accommodation of the β-stereoisomers within the polymerase was noted, suggesting that these stereoisomers would be more prone to cause blockage. Stereochemistry-dependent differences in adduct orientation could be expected to produce different biochemical effects, as has been observed in adducts derived from polycyclic aromatic hydrocarbons.",
author = "Lihua Wang and Hingerty, {Brian E.} and Robert Shapiro and Suse Broyde",
year = "2004",
month = "3",
doi = "10.1021/tx034218l",
language = "English (US)",
volume = "17",
pages = "311--324",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
number = "3",

}

TY - JOUR

T1 - Structural and Stereoisomer Effects of Model Estrogen Quinone-Derived DNA Adducts

T2 - N6-(2-Hydroxyestron-6(α,β)-yl)-2′ -deoxyadenosine and N2-(2-Hydroxyestron-6(α,β )-yl)-2′-deoxyguanosine

AU - Wang, Lihua

AU - Hingerty, Brian E.

AU - Shapiro, Robert

AU - Broyde, Suse

PY - 2004/3

Y1 - 2004/3

N2 - An extensive conformational analysis has been carried out for two diastereoisomeric pairs of model estrogen quinone-derived DNA adducts, N 6-(2-hydroxyestron-6(α,β)-yl)-2′-deoxyadenosine (2-OHE1-6(α,β)-N6-dA) and N 2-(2-hydroxyestron-6(α,β)-yl)-2′-deoxyguanosine (2-OHE1-6(α,β)-N2-dG), in a B-DNA duplex and at a primer-template junction in a pol α family DNA polymerase. In vitro primer extension studies in pol α [Terashima, I., et al. (1998) Biochemistry 37, 13807-13815] have shown that the adenine adducts can incorporate dT, together with a small proportion of the incorrect base dC opposite the lesion, and they block less strongly than the guanine adducts. We have carried out conformational searches with energy minimization for four DNA duplexes containing 2-OHE1-6α-N6-dA, 2-OHE 1-6β-N6-dA, 2-OHE1-6α-N 2-dG, or 2-OHE1-6β-N2-dG. Our searches revealed that the four-ring nonplanar 2-hydroxyestrone (2-OHE1) moiety strongly prefers to reside in the major groove of the adenine adducts or the minor groove of the guanine adducts in a B-DNA duplex, with stereochemistry-dependent orientational differences in each case. No low energy conformations involving intercalation of the 2-OHE1 moiety were located in the searches. This stems from the largely nonplanar, nonaromatic nature of the 2-OHE1 ring system and implies that the proclivity for such bulky, nonplanar adducts to reside at the DNA helix exterior is a plausible conformational feature of other structurally similar estrogen quinone-derived DNA adducts, independent of base sequence context. In addition, the adenine adduct isomers, located in the major groove, manifest serious disturbance to the Watson-Crick base pairs at and near the lesion site, suggesting repair susceptibility. Possible structures of these adducts in a pol α family polymerase were also investigated through molecular modeling. The results rationalized the experimental in vitro primer extension studies. In addition, poor accommodation of the β-stereoisomers within the polymerase was noted, suggesting that these stereoisomers would be more prone to cause blockage. Stereochemistry-dependent differences in adduct orientation could be expected to produce different biochemical effects, as has been observed in adducts derived from polycyclic aromatic hydrocarbons.

AB - An extensive conformational analysis has been carried out for two diastereoisomeric pairs of model estrogen quinone-derived DNA adducts, N 6-(2-hydroxyestron-6(α,β)-yl)-2′-deoxyadenosine (2-OHE1-6(α,β)-N6-dA) and N 2-(2-hydroxyestron-6(α,β)-yl)-2′-deoxyguanosine (2-OHE1-6(α,β)-N2-dG), in a B-DNA duplex and at a primer-template junction in a pol α family DNA polymerase. In vitro primer extension studies in pol α [Terashima, I., et al. (1998) Biochemistry 37, 13807-13815] have shown that the adenine adducts can incorporate dT, together with a small proportion of the incorrect base dC opposite the lesion, and they block less strongly than the guanine adducts. We have carried out conformational searches with energy minimization for four DNA duplexes containing 2-OHE1-6α-N6-dA, 2-OHE 1-6β-N6-dA, 2-OHE1-6α-N 2-dG, or 2-OHE1-6β-N2-dG. Our searches revealed that the four-ring nonplanar 2-hydroxyestrone (2-OHE1) moiety strongly prefers to reside in the major groove of the adenine adducts or the minor groove of the guanine adducts in a B-DNA duplex, with stereochemistry-dependent orientational differences in each case. No low energy conformations involving intercalation of the 2-OHE1 moiety were located in the searches. This stems from the largely nonplanar, nonaromatic nature of the 2-OHE1 ring system and implies that the proclivity for such bulky, nonplanar adducts to reside at the DNA helix exterior is a plausible conformational feature of other structurally similar estrogen quinone-derived DNA adducts, independent of base sequence context. In addition, the adenine adduct isomers, located in the major groove, manifest serious disturbance to the Watson-Crick base pairs at and near the lesion site, suggesting repair susceptibility. Possible structures of these adducts in a pol α family polymerase were also investigated through molecular modeling. The results rationalized the experimental in vitro primer extension studies. In addition, poor accommodation of the β-stereoisomers within the polymerase was noted, suggesting that these stereoisomers would be more prone to cause blockage. Stereochemistry-dependent differences in adduct orientation could be expected to produce different biochemical effects, as has been observed in adducts derived from polycyclic aromatic hydrocarbons.

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