NMR evidence for syn-anti interconversion of a trans opened (10R)-dA adduct of benzo[a]pyrene (7S,8R)-diol (9R,10S)-epoxide in a DNA duplex

D. E. Volk, J. S. Rice, B. A. Luxon, H. J C Yeh, C. Liang, G. Xie, J. M. Sayer, D. M. Jerina, D. G. Gorenstein

    Research output: Contribution to journalArticle

    47 Citations (Scopus)

    Abstract

    2D NMR has been used to examine the structure and dynamics of a 12-mer DNA duplex, d(T1A2G3T4C5A6A7*G8G9G10C11A12)-d(T13G14C15C16C17T 18T19G20A21C22T23A24), containing a 10R adduct at dA*7 that corresponds to trans addition of the N6-amino group of dA7 to (-)-(7S,8R,9R,10S)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(-)-(S,R,R,S)-BP DE-2]. This DNA duplex contains the base sequence for the major dA mutational hot spot in the HPRT gene when Chinese hamster V79 cells are given low doses of the highly carcinogenic (+)-(R,S,S,R)-BP DE-2 enantiomer. NOE data indicate that the hydrocarbon is intercalated on the 5'-side of the modified base as has been seen previously for other oligonucleotides containing BP DE-2 (10R)-dA adducts. 2D chemical exchange-only experiments indicate dynamic behavior near the intercalation site especially at the 10R adducted dA, such that this base interconverts between the normal anti conformation and a less populated syn conformation. Ab initio molecular orbital chemical shift calculations of nucleotide and dinucleotide fragments in the syn and anti conformations support these conclusions. Although this DNA duplex containing a 10R dA adduct exhibits conformational flexibility as described, it is nevertheless more conformationally stable than the corresponding 10S adducted duplex corresponding to trans opening of the carcinogenic isomer (+)-(R,S,S,R)-BP DE-2, which was too dynamic to permit NMR structure determination. UV and imino proton NMR spectral observations indicated pronounced differences between these two diastereomeric 12-mer duplexes, consistent with conformational disorder at the adduct site and/or an equilibrium with a nonintercalated orientation of the hydrocarbon in the duplex containing the 10S adduct. The existence of conformational flexibility around adducts may be related to the occurrence of multiple mutagenic outcomes resulting from a single DE adduct.

    Original languageEnglish (US)
    Pages (from-to)14040-14053
    Number of pages14
    JournalBiochemistry
    Volume39
    Issue number46
    DOIs
    StatePublished - Nov 21 2000

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    Benzo(a)pyrene
    Epoxy Compounds
    Conformations
    Nuclear magnetic resonance
    Hydrocarbons
    DNA
    7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
    Hypoxanthine Phosphoribosyltransferase
    Enantiomers
    Chemical shift
    Molecular orbitals
    Intercalation
    Cricetulus
    Oligonucleotides
    Isomers
    Protons
    Nucleotides
    Genes
    Experiments

    ASJC Scopus subject areas

    • Biochemistry

    Cite this

    Volk, D. E., Rice, J. S., Luxon, B. A., Yeh, H. J. C., Liang, C., Xie, G., ... Gorenstein, D. G. (2000). NMR evidence for syn-anti interconversion of a trans opened (10R)-dA adduct of benzo[a]pyrene (7S,8R)-diol (9R,10S)-epoxide in a DNA duplex. Biochemistry, 39(46), 14040-14053. https://doi.org/10.1021/bi001669l

    NMR evidence for syn-anti interconversion of a trans opened (10R)-dA adduct of benzo[a]pyrene (7S,8R)-diol (9R,10S)-epoxide in a DNA duplex. / Volk, D. E.; Rice, J. S.; Luxon, B. A.; Yeh, H. J C; Liang, C.; Xie, G.; Sayer, J. M.; Jerina, D. M.; Gorenstein, D. G.

    In: Biochemistry, Vol. 39, No. 46, 21.11.2000, p. 14040-14053.

    Research output: Contribution to journalArticle

    Volk, DE, Rice, JS, Luxon, BA, Yeh, HJC, Liang, C, Xie, G, Sayer, JM, Jerina, DM & Gorenstein, DG 2000, 'NMR evidence for syn-anti interconversion of a trans opened (10R)-dA adduct of benzo[a]pyrene (7S,8R)-diol (9R,10S)-epoxide in a DNA duplex', Biochemistry, vol. 39, no. 46, pp. 14040-14053. https://doi.org/10.1021/bi001669l
    Volk, D. E. ; Rice, J. S. ; Luxon, B. A. ; Yeh, H. J C ; Liang, C. ; Xie, G. ; Sayer, J. M. ; Jerina, D. M. ; Gorenstein, D. G. / NMR evidence for syn-anti interconversion of a trans opened (10R)-dA adduct of benzo[a]pyrene (7S,8R)-diol (9R,10S)-epoxide in a DNA duplex. In: Biochemistry. 2000 ; Vol. 39, No. 46. pp. 14040-14053.
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    abstract = "2D NMR has been used to examine the structure and dynamics of a 12-mer DNA duplex, d(T1A2G3T4C5A6A7*G8G9G10C11A12)-d(T13G14C15C16C17T 18T19G20A21C22T23A24), containing a 10R adduct at dA*7 that corresponds to trans addition of the N6-amino group of dA7 to (-)-(7S,8R,9R,10S)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(-)-(S,R,R,S)-BP DE-2]. This DNA duplex contains the base sequence for the major dA mutational hot spot in the HPRT gene when Chinese hamster V79 cells are given low doses of the highly carcinogenic (+)-(R,S,S,R)-BP DE-2 enantiomer. NOE data indicate that the hydrocarbon is intercalated on the 5'-side of the modified base as has been seen previously for other oligonucleotides containing BP DE-2 (10R)-dA adducts. 2D chemical exchange-only experiments indicate dynamic behavior near the intercalation site especially at the 10R adducted dA, such that this base interconverts between the normal anti conformation and a less populated syn conformation. Ab initio molecular orbital chemical shift calculations of nucleotide and dinucleotide fragments in the syn and anti conformations support these conclusions. Although this DNA duplex containing a 10R dA adduct exhibits conformational flexibility as described, it is nevertheless more conformationally stable than the corresponding 10S adducted duplex corresponding to trans opening of the carcinogenic isomer (+)-(R,S,S,R)-BP DE-2, which was too dynamic to permit NMR structure determination. UV and imino proton NMR spectral observations indicated pronounced differences between these two diastereomeric 12-mer duplexes, consistent with conformational disorder at the adduct site and/or an equilibrium with a nonintercalated orientation of the hydrocarbon in the duplex containing the 10S adduct. The existence of conformational flexibility around adducts may be related to the occurrence of multiple mutagenic outcomes resulting from a single DE adduct.",
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    T1 - NMR evidence for syn-anti interconversion of a trans opened (10R)-dA adduct of benzo[a]pyrene (7S,8R)-diol (9R,10S)-epoxide in a DNA duplex

    AU - Volk, D. E.

    AU - Rice, J. S.

    AU - Luxon, B. A.

    AU - Yeh, H. J C

    AU - Liang, C.

    AU - Xie, G.

    AU - Sayer, J. M.

    AU - Jerina, D. M.

    AU - Gorenstein, D. G.

    PY - 2000/11/21

    Y1 - 2000/11/21

    N2 - 2D NMR has been used to examine the structure and dynamics of a 12-mer DNA duplex, d(T1A2G3T4C5A6A7*G8G9G10C11A12)-d(T13G14C15C16C17T 18T19G20A21C22T23A24), containing a 10R adduct at dA*7 that corresponds to trans addition of the N6-amino group of dA7 to (-)-(7S,8R,9R,10S)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(-)-(S,R,R,S)-BP DE-2]. This DNA duplex contains the base sequence for the major dA mutational hot spot in the HPRT gene when Chinese hamster V79 cells are given low doses of the highly carcinogenic (+)-(R,S,S,R)-BP DE-2 enantiomer. NOE data indicate that the hydrocarbon is intercalated on the 5'-side of the modified base as has been seen previously for other oligonucleotides containing BP DE-2 (10R)-dA adducts. 2D chemical exchange-only experiments indicate dynamic behavior near the intercalation site especially at the 10R adducted dA, such that this base interconverts between the normal anti conformation and a less populated syn conformation. Ab initio molecular orbital chemical shift calculations of nucleotide and dinucleotide fragments in the syn and anti conformations support these conclusions. Although this DNA duplex containing a 10R dA adduct exhibits conformational flexibility as described, it is nevertheless more conformationally stable than the corresponding 10S adducted duplex corresponding to trans opening of the carcinogenic isomer (+)-(R,S,S,R)-BP DE-2, which was too dynamic to permit NMR structure determination. UV and imino proton NMR spectral observations indicated pronounced differences between these two diastereomeric 12-mer duplexes, consistent with conformational disorder at the adduct site and/or an equilibrium with a nonintercalated orientation of the hydrocarbon in the duplex containing the 10S adduct. The existence of conformational flexibility around adducts may be related to the occurrence of multiple mutagenic outcomes resulting from a single DE adduct.

    AB - 2D NMR has been used to examine the structure and dynamics of a 12-mer DNA duplex, d(T1A2G3T4C5A6A7*G8G9G10C11A12)-d(T13G14C15C16C17T 18T19G20A21C22T23A24), containing a 10R adduct at dA*7 that corresponds to trans addition of the N6-amino group of dA7 to (-)-(7S,8R,9R,10S)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(-)-(S,R,R,S)-BP DE-2]. This DNA duplex contains the base sequence for the major dA mutational hot spot in the HPRT gene when Chinese hamster V79 cells are given low doses of the highly carcinogenic (+)-(R,S,S,R)-BP DE-2 enantiomer. NOE data indicate that the hydrocarbon is intercalated on the 5'-side of the modified base as has been seen previously for other oligonucleotides containing BP DE-2 (10R)-dA adducts. 2D chemical exchange-only experiments indicate dynamic behavior near the intercalation site especially at the 10R adducted dA, such that this base interconverts between the normal anti conformation and a less populated syn conformation. Ab initio molecular orbital chemical shift calculations of nucleotide and dinucleotide fragments in the syn and anti conformations support these conclusions. Although this DNA duplex containing a 10R dA adduct exhibits conformational flexibility as described, it is nevertheless more conformationally stable than the corresponding 10S adducted duplex corresponding to trans opening of the carcinogenic isomer (+)-(R,S,S,R)-BP DE-2, which was too dynamic to permit NMR structure determination. UV and imino proton NMR spectral observations indicated pronounced differences between these two diastereomeric 12-mer duplexes, consistent with conformational disorder at the adduct site and/or an equilibrium with a nonintercalated orientation of the hydrocarbon in the duplex containing the 10S adduct. The existence of conformational flexibility around adducts may be related to the occurrence of multiple mutagenic outcomes resulting from a single DE adduct.

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