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.

  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.},
  author={Carlos R. de los Santos and Monique Cosman and Brian E. Hingerty and V{\'i}ctor Ib{\'a}{\~n}ez and Leonid A. Margulis and Nicholas E. Geacintov and Suse Broyde and Dinshaw J. Patel},
  volume={31 23},
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… 

Structural characterization of a (+)-trans-anti-benzo[a]pyrene-DNA adduct using NMR, restrained energy minimization, and molecular dynamics.

A DNA duplex containing a (+)-trans-anti-benzo[a]pyrene adduct covalently attached to the G8 nucleotide in the sequence d(CCTATGT[BP-G]CAC) was synthesized and the structure characterized by one- and two-dimensional NMR spectroscopy, in conjunction with energy minimization and molecular dynamics simulations.

Solution conformation of the (+)-trans-anti-[BPh]dA adduct opposite dT in a DNA duplex: intercalation of the covalently attached benzo[c]phenanthrene to the 5'-side of the adduct site without disruption of the modified base pair.

The structure provides new insights into how a polycyclic aromatic hydrocarbon covalently attached to the major groove edge of deoxyadenosine can still unidirectionally intercalate into the helix without disruption of the modified base pair.

Mutagenesis studies with four stereoisomeric N2-dG benzo[a]pyrene adducts in the identical 5'-CGC sequence used in NMR studies: G->T mutations dominate in each case.

It is suggested that adduct conformation must be fluid enough in the 5'-CGC sequence that the duplex DNA conformation can interconvert to mutagenic and non-mutagenic conformations during lesion-bypass.

Solution conformation of the (+)-trans-anti-benzo[g]chrysene-dA adduct opposite dT in a DNA duplex.

The results established that the covalently attached benzo[g]chrysene ring intercalates into the DNA helix directed towards the 5'-side of the modified strand and stacks predominantly with dT17 when intercalated between dC5.dT17 base-pair.

Nuclear Magnetic Resonance Studies of an N2-Guanine Adduct Derived from the Tumorigen Dibenzo[a,l]pyrene in DNA: Impact of Adduct Stereochemistry, Size, and Local DNA Sequence on Solution Conformations

Investigation of the 14S-DB[a,l]P-N2-dG adduct in two different sequence contexts using NMR methods with distance-restrained molecular dynamics simulations broadens the understanding of the structure–function relationship in NER.

Crystal and molecular structure of a benzo[a]pyrene 7,8-diol 9,10-epoxide N2-deoxyguanosine adduct: absolute configuration and conformation.

The crystal structure of such an adduct at the exocyclic amino group of a purine nucleoside is described, showing independent and unambiguous proof of the absolute configuration of the adduct based on the spatial relationship between the known chiral carbon atoms of the deoxyribose and the four asymmetric centers in the hydrocarbon moiety.

Benzo[a]pyrene diol epoxide-DNA cis adduct formation through a trans chlorohydrin intermediate.

Results support a mechanism by which chloride ion undergoes nucleophilic addition to the benzylic C-10 position of anti-BPDE that generates a trans halohydrin that alkylates DNA with inversion of configuration to form a cis adduct.

Molecular modeling of the major adduct of (+)-anti-B[a]PDE (N2-dG) in the eight conformations and the five DNA sequences most relevant to base substitution mutagenesis.

Eight conformations are deemed most likely to be relevant to mutagenesis and are excluded by systematically varying several parameters (such as the initial annealing temperature) based on a protocol established recently to exclude conformations that are clearly inferior.

Nuclear magnetic resonance solution structure of an N(2)-guanine DNA adduct derived from the potent tumorigen dibenzo[a,l]pyrene: intercalation from the minor groove with ruptured Watson-Crick base pairing.

This new theme in PAH DE-DNA adduct conformation differs from (1) the classical intercalation motif in which Watson-Crick base pairing is intact at the lesion site and (2) the base-displaced intercalators in which the damaged base and its partner are extruded from the helix.



Solution conformation of the major adduct between the carcinogen (+)-anti-benzo[a]pyrene diol epoxide and DNA.

The solution structure centered about the BP covalent adduct site in the (BP)G.C 11-mer duplex is determined by incorporating intramolecular and intermolecular proton-proton distance bounds deduced from the NMR data sets as constraints in energy minimization computations.

Dependence of conformations of benzo[a]pyrene diol epoxide-DNA adducts derived from stereoisomers of different tumorigenicities on base sequence.

The conformations of covalent adducts derived from the binding of the highly tumorigenic stereoisomer (+)-trans- 7,8-dihydroxy-anti-9,10-epoxy-7,8,9, 10-tetrahydrobenzo[a]pyren e and its nontumorigenic (-)-anti-BPDE isomer were investigated by employing UV absorbance and linear dichroism methods.

Stereoselective covalent binding of anti-benzo(a)pyrene diol epoxide to DNA conformation of enantiomer adducts.

Findings support the proposals by Brookes and Osborne that the difference in spatial orientation of the N2-dG adducts of (-)-anti-BaPDE together with their lower abundance may account for the lower biological activity of the (-) enantiomer.

Spectroscopic characteristics and site I/site II classification of cis and trans benzo[a]pyrene diolepoxide enantiomer-guanosine adducts in oligonucleotides and polynucleotides.

The spectroscopic characteristics of these BPDE-modified polynucleotide adducts are consistent with those of the BPDe-modified oligonucleotide complexes; the cis adductS are correlated with site I adduct conformations, while the trans adduct's are of the site II type.

Binding of benzo[a]pyrene 7,8-diol-9,10-epoxides to DNA, RNA, and protein of mouse skin occurs with high stereoselectivity.

Polymer adducts from diastereomeric diol epoxides were formed stereospecifically from their corresponding 7,8-dihydrodiols, and binding occurs preferentially at the 2-amino group of guanine in cellular RNA and DNA in vivo.

Preparation and isolation of adducts in high yield derived from the binding of two benzo[a]pyrene-7,8-dihydroxy-9,10-oxide stereoisomers to the oligonucleotide d(ATATGTATA).

These relatively high reaction efficiencies offer the possibilities of synthesizing relatively large amounts of well-defined covalent BPDE-oligonucleotide adducts (with different sequences of nucleotides flanking the modified base) for detailed spectroscopic and biochemical studies.

Double-stranded DNA stereoselectively binds benzo(a)pyrene diol epoxides

The enantiomers of (±) anti-BP diol epoxide are resolved and the optically pure hydrocarbons with DNA are reacted and the basis for the stereoselective binding is unknown but may involve formation of sterically orientated physical complexes before covalent attachment of the hydrocarbon to DNA.

Covalent binding of (+)- and (-)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyr ene to B and Z DNAs.

  • F. Chen
  • Chemistry, Biology
  • 1985
Evidence suggests that covalent modification by anti-BPDE inhibits the B to Z conversion of base pairs in its immediate vicinity, presumably through intercalative stabilization of the B conformer at high salt.

Spectroscopic studies of DNA complexes formed after reaction with anti-benzo[a]pyrene-7,8-dihydrodiol-9,10-oxide enantiomers of different carcinogenic potency.

Since DNA-binding of chemical carcinogens is considered crucial for tumour initiation it follows that the unique properties of the type II BPDE-DNA complex may be of fundamental importance in benzo[a]pyrene carcinogenesis.

NMR and computational characterization of the N-(deoxyguanosin-8-yl)aminofluorene adduct [(AF)G] opposite adenosine in DNA: (AF)G[syn].A[anti] pair formation and its pH dependence.

The exchangeable and nonexchangeable protons are well resolved and narrow in the NMR spectra of the (AF)G 11-mer duplex so that the base and the majority of sugar nucleic acid protons, as well as several aminofluorene ring protons have been assigned following analysis of two-dimensional NOESY and COSY data sets.