Influence of benzo[a]pyrene diol epoxide chirality on solution conformations of DNA covalent adducts: The (-)-trans-anti-[BP]G·C adduct structure and comparison with the (+)-trans-anti-[BP]G·C enantiomer

Carlos De Los Santos, Monique Cosman, Brian E. Hingerty, Victor Ibanez, Leonid A. Margulis, Nicholas E. Geacintov, Suse Broyde, Dinshaw J. Patel

Research output: Contribution to journalArticle

Abstract

Benzo[a]pyrene (BP) is an environmental genotoxin, which, following metabolic activation to 7,8-diol 9,10-epoxide (BPDE) derivatives, forms covalent adducts with cellular DNA. A major fraction of adducts are derived from the binding of N2 of guanine to the C10 position of BPDE. The mutagenic and carcinogenic potentials of these adducts are strongly dependent on the chirality at the four asymmetric benzylic carbon atoms. We report below on the combined NMR-energy minimization refinement characterization of the solution conformation of (-)-trans-anti-[BP]G positioned opposite C and flanked by G·C base pairs in the d(C1-C2-A3-T4-C5-[BP]G6-C7-T8-A9-C10-C11)·d(G12-G13-T14-A15-G16-C17-G18- A19-T20-G21-G22) duplex. Two-dimensional NMR techniques were applied to assign the exchangeable and non-exchangeable protons of the benzo[a]pyrenyl moiety and the nucleic acid in the modified duplex. These results establish Watson-Crick base pair alignment at the [BP]G6·C17 modification site, as well as the flanking C5·G18 and C7·G16 pairs within a regular right-handed helix. The solution structure of the (-)-trans-anti-[BP]G·C 11-mer duplex has been determined by incorporating intramolecular and intermolecular proton-proton distances defined by lower and upper bounds deduced from NOE buildup curves as constraints in energy minimization computations. The BP ring spans both strands of the duplex in the minor groove and is directed toward the 3′-end of the modified strand in the refined structure. One face of the BP ring of [BP]G6 stacks over the C17 residue across from it on the partner strand while the other face is exposed to solvent. The long axis of the BP ring makes an angle of approximately 40° with the average direction of the DNA helix axis and is readily accommodated within a widened minor groove of a minimally perturbed B-DNA helix. The present results on the (-)-trans-anti-BP-N2-G adduct opposite C in which the BP ring is oriented toward the 3′-end of the modified strand contrast strikingly with our previous demonstration that the mirror image (+)-trans-anti stereoisomer within the same sequence context orients the BP ring toward the 5′-end of the modified strand [Cosman et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918]. These orientational differences are due to the chiral characteristics of the two BPDE enantiomers and may have profound influences on the interaction of cellular enzyme systems with these two structurally different alignments of this bulky DNA lesion.

Original languageEnglish (US)
Pages (from-to)5245-5252
Number of pages8
JournalBiochemistry
Volume31
Issue number23
StatePublished - 1992

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7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
Enantiomers
DNA Adducts
Chirality
Benzo(a)pyrene
Epoxy Compounds
Conformations
Protons
Base Pairing
DNA
Nuclear magnetic resonance
B-Form DNA
Stereoisomerism
Mutagens
Guanine
Nucleic Acids
Mirrors
Demonstrations
Carbon
Chemical activation

ASJC Scopus subject areas

  • Biochemistry

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Influence of benzo[a]pyrene diol epoxide chirality on solution conformations of DNA covalent adducts : The (-)-trans-anti-[BP]G·C adduct structure and comparison with the (+)-trans-anti-[BP]G·C enantiomer. / De Los Santos, Carlos; Cosman, Monique; Hingerty, Brian E.; Ibanez, Victor; Margulis, Leonid A.; Geacintov, Nicholas E.; Broyde, Suse; Patel, Dinshaw J.

In: Biochemistry, Vol. 31, No. 23, 1992, p. 5245-5252.

Research output: Contribution to journalArticle

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title = "Influence of benzo[a]pyrene diol epoxide chirality on solution conformations of DNA covalent adducts: The (-)-trans-anti-[BP]G·C adduct structure and comparison with the (+)-trans-anti-[BP]G·C enantiomer",
abstract = "Benzo[a]pyrene (BP) is an environmental genotoxin, which, following metabolic activation to 7,8-diol 9,10-epoxide (BPDE) derivatives, forms covalent adducts with cellular DNA. A major fraction of adducts are derived from the binding of N2 of guanine to the C10 position of BPDE. The mutagenic and carcinogenic potentials of these adducts are strongly dependent on the chirality at the four asymmetric benzylic carbon atoms. We report below on the combined NMR-energy minimization refinement characterization of the solution conformation of (-)-trans-anti-[BP]G positioned opposite C and flanked by G·C base pairs in the d(C1-C2-A3-T4-C5-[BP]G6-C7-T8-A9-C10-C11)·d(G12-G13-T14-A15-G16-C17-G18- A19-T20-G21-G22) duplex. Two-dimensional NMR techniques were applied to assign the exchangeable and non-exchangeable protons of the benzo[a]pyrenyl moiety and the nucleic acid in the modified duplex. These results establish Watson-Crick base pair alignment at the [BP]G6·C17 modification site, as well as the flanking C5·G18 and C7·G16 pairs within a regular right-handed helix. The solution structure of the (-)-trans-anti-[BP]G·C 11-mer duplex has been determined by incorporating intramolecular and intermolecular proton-proton distances defined by lower and upper bounds deduced from NOE buildup curves as constraints in energy minimization computations. The BP ring spans both strands of the duplex in the minor groove and is directed toward the 3′-end of the modified strand in the refined structure. One face of the BP ring of [BP]G6 stacks over the C17 residue across from it on the partner strand while the other face is exposed to solvent. The long axis of the BP ring makes an angle of approximately 40° with the average direction of the DNA helix axis and is readily accommodated within a widened minor groove of a minimally perturbed B-DNA helix. The present results on the (-)-trans-anti-BP-N2-G adduct opposite C in which the BP ring is oriented toward the 3′-end of the modified strand contrast strikingly with our previous demonstration that the mirror image (+)-trans-anti stereoisomer within the same sequence context orients the BP ring toward the 5′-end of the modified strand [Cosman et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918]. These orientational differences are due to the chiral characteristics of the two BPDE enantiomers and may have profound influences on the interaction of cellular enzyme systems with these two structurally different alignments of this bulky DNA lesion.",
author = "{De Los Santos}, Carlos and Monique Cosman and Hingerty, {Brian E.} and Victor Ibanez and Margulis, {Leonid A.} and Geacintov, {Nicholas E.} and Suse Broyde and Patel, {Dinshaw J.}",
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T1 - Influence of benzo[a]pyrene diol epoxide chirality on solution conformations of DNA covalent adducts

T2 - The (-)-trans-anti-[BP]G·C adduct structure and comparison with the (+)-trans-anti-[BP]G·C enantiomer

AU - De Los Santos, Carlos

AU - Cosman, Monique

AU - Hingerty, Brian E.

AU - Ibanez, Victor

AU - Margulis, Leonid A.

AU - Geacintov, Nicholas E.

AU - Broyde, Suse

AU - Patel, Dinshaw J.

PY - 1992

Y1 - 1992

N2 - Benzo[a]pyrene (BP) is an environmental genotoxin, which, following metabolic activation to 7,8-diol 9,10-epoxide (BPDE) derivatives, forms covalent adducts with cellular DNA. A major fraction of adducts are derived from the binding of N2 of guanine to the C10 position of BPDE. The mutagenic and carcinogenic potentials of these adducts are strongly dependent on the chirality at the four asymmetric benzylic carbon atoms. We report below on the combined NMR-energy minimization refinement characterization of the solution conformation of (-)-trans-anti-[BP]G positioned opposite C and flanked by G·C base pairs in the d(C1-C2-A3-T4-C5-[BP]G6-C7-T8-A9-C10-C11)·d(G12-G13-T14-A15-G16-C17-G18- A19-T20-G21-G22) duplex. Two-dimensional NMR techniques were applied to assign the exchangeable and non-exchangeable protons of the benzo[a]pyrenyl moiety and the nucleic acid in the modified duplex. These results establish Watson-Crick base pair alignment at the [BP]G6·C17 modification site, as well as the flanking C5·G18 and C7·G16 pairs within a regular right-handed helix. The solution structure of the (-)-trans-anti-[BP]G·C 11-mer duplex has been determined by incorporating intramolecular and intermolecular proton-proton distances defined by lower and upper bounds deduced from NOE buildup curves as constraints in energy minimization computations. The BP ring spans both strands of the duplex in the minor groove and is directed toward the 3′-end of the modified strand in the refined structure. One face of the BP ring of [BP]G6 stacks over the C17 residue across from it on the partner strand while the other face is exposed to solvent. The long axis of the BP ring makes an angle of approximately 40° with the average direction of the DNA helix axis and is readily accommodated within a widened minor groove of a minimally perturbed B-DNA helix. The present results on the (-)-trans-anti-BP-N2-G adduct opposite C in which the BP ring is oriented toward the 3′-end of the modified strand contrast strikingly with our previous demonstration that the mirror image (+)-trans-anti stereoisomer within the same sequence context orients the BP ring toward the 5′-end of the modified strand [Cosman et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918]. These orientational differences are due to the chiral characteristics of the two BPDE enantiomers and may have profound influences on the interaction of cellular enzyme systems with these two structurally different alignments of this bulky DNA lesion.

AB - Benzo[a]pyrene (BP) is an environmental genotoxin, which, following metabolic activation to 7,8-diol 9,10-epoxide (BPDE) derivatives, forms covalent adducts with cellular DNA. A major fraction of adducts are derived from the binding of N2 of guanine to the C10 position of BPDE. The mutagenic and carcinogenic potentials of these adducts are strongly dependent on the chirality at the four asymmetric benzylic carbon atoms. We report below on the combined NMR-energy minimization refinement characterization of the solution conformation of (-)-trans-anti-[BP]G positioned opposite C and flanked by G·C base pairs in the d(C1-C2-A3-T4-C5-[BP]G6-C7-T8-A9-C10-C11)·d(G12-G13-T14-A15-G16-C17-G18- A19-T20-G21-G22) duplex. Two-dimensional NMR techniques were applied to assign the exchangeable and non-exchangeable protons of the benzo[a]pyrenyl moiety and the nucleic acid in the modified duplex. These results establish Watson-Crick base pair alignment at the [BP]G6·C17 modification site, as well as the flanking C5·G18 and C7·G16 pairs within a regular right-handed helix. The solution structure of the (-)-trans-anti-[BP]G·C 11-mer duplex has been determined by incorporating intramolecular and intermolecular proton-proton distances defined by lower and upper bounds deduced from NOE buildup curves as constraints in energy minimization computations. The BP ring spans both strands of the duplex in the minor groove and is directed toward the 3′-end of the modified strand in the refined structure. One face of the BP ring of [BP]G6 stacks over the C17 residue across from it on the partner strand while the other face is exposed to solvent. The long axis of the BP ring makes an angle of approximately 40° with the average direction of the DNA helix axis and is readily accommodated within a widened minor groove of a minimally perturbed B-DNA helix. The present results on the (-)-trans-anti-BP-N2-G adduct opposite C in which the BP ring is oriented toward the 3′-end of the modified strand contrast strikingly with our previous demonstration that the mirror image (+)-trans-anti stereoisomer within the same sequence context orients the BP ring toward the 5′-end of the modified strand [Cosman et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918]. These orientational differences are due to the chiral characteristics of the two BPDE enantiomers and may have profound influences on the interaction of cellular enzyme systems with these two structurally different alignments of this bulky DNA lesion.

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