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Chem Res Toxicol. 2006 Feb;19(2):195-208.

Stereospecific formation of interstrand carbinolamine DNA cross-links by crotonaldehyde- and acetaldehyde-derived alpha-CH3-gamma-OH-1,N2-propano-2'-deoxyguanosine adducts in the 5'-CpG-3' sequence.

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  • 1Department of Chemistry, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, USA.


The crotonaldehyde- and acetaldehyde-derived R- and S-alpha-CH3-gamma-OH-1,N2-propanodeoxyguanosine adducts were monitored in single-stranded and duplex oligodeoxynucleotides using NMR spectroscopy. In both instances, the cis and trans diastereomers of the alpha-CH3 and gamma-OH groups underwent slow exchange, with the trans diastereomers being favored. In single-stranded oligodeoxynucleotides, the aldehyde intermediates were not detected spectroscopically, but their presence was revealed through the formation of N-terminal conjugates with the tetrapeptide KWKK. When annealed into 5'-d(GCTAGCXAGTCC)-3'.5'-d(GGACTCYCTAGC)-3' containing the 5'-CpG-3' sequence context (X = R- or S-alpha-CH3-gamma-13C-OH-PdG; Y = 15N2-dG) at pH 7, partial opening of the R- or S-alpha-CH3-gamma-13C-OH-PdG adducts to the corresponding N2-(3-oxo-1-methyl-propyl)-dG aldehydes was observed at temperatures below the T(m) of the duplexes. These aldehydes equilibrated with their geminal diol hydrates; higher temperatures favored the aldehydes. When annealed opposite T, the S-alpha-CH3-gamma-13C-OH-PdG adduct was stable. At 37 degrees C, an interstrand DNA cross-link was observed spectroscopically only for the R-alpha-CH3-gamma-OH-PdG adduct. Molecular modeling predicted that the interstrand cross-link formed by the R-alpha-CH3-gamma-OH-PdG adduct introduced less disruption into the duplex structure than did the cross-link arising from the S-alpha-CH3-gamma-OH-PdG adduct, due to differing orientations of the R- and S-CH3 groups. Modeling also predicted that the alpha-methyl group of the aldehyde arising from the R-alpha-CH3-gamma-OH-PdG adduct is oriented in the 3'-direction in the minor groove, facilitating cross-linking. In contrast, the alpha-methyl group of the aldehyde arising from the S-alpha-CH3-gamma-OH-PdG adduct is oriented in the 5'-direction within the minor groove, potentially hindering cross-linking. NMR revealed that for the R-alpha-CH3-gamma-OH-PdG adduct, the carbinolamine form of the cross-link was favored in duplex DNA with the imine (Schiff base) form of the cross-link remaining below the level of spectroscopic detection. Molecular modeling predicted that the carbinolamine linkage maintained Watson-Crick hydrogen bonding at both of the tandem C.G base pairs. Dehydration of the carbinolamine cross-link to an imine, or cyclization of the latter to form a pyrimidopurinone cross-link, required disruption of Watson-Crick hydrogen bonding at one or both of the cross-linked base pairs.

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