title: Chemical properties of oxopropenyl adducts of purine and pyrimidine nucleosides and their reactivity toward amino acid cross-link formation.
abstract: N2-oxopropenyldeoxyguanosine (2) forms in duplex DNA by modification of dG residues with base propenal or malondialdehyde. The pKa of 2 was estimated to be 6.9 from the pH dependence of its ring-closing to the pyrimidopurinone derivative 1. The acidity of 2 may be an important determinant of its miscoding properties and its reactivity to nucleophiles in DNA or protein. To test this hypothesis, analogous N-oxopropenyl derivatives of dA (4), dC (5), and N1-methyl-dG (6) were synthesized and their pKa's were determined by optical titration. The N-oxopropenyl derivatives of dA and dC both exhibited pKa's of 10.5, whereas the N-oxopropenyl derivative of N1-methyldG exhibited a pKa of 8.2. Cross-linking of 2, 4, 5, and 6 to N(alpha)-acetyl-lysine was explored at neutral pH. Adduct 2 did not react with N(alpha)-acetyl-lysine, whereas 4-6 readily formed cross-links. The structures of the cross-links were elucidated, and their stabilities were investigated. The results define the acidity of oxopropenyl deoxynucleosides and highlight its importance to their reactivity toward nucleophiles. This study also identifies the structures of a potential novel class of DNA-protein cross-links.
authors.affiliation: Department of Chemistry, Center in Molecular Toxicology, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235-1822, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Szekely
authors.forename: Carmelo J
authors.initials: CJ
authors.lastname: Rizzo
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry*; D003849:Deoxyguanosine / Q000031:analogs & derivatives*; D007700:Kinetics; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry; D008315:Malondialdehyde / Q000031:analogs & derivatives / Q000737:chemistry; D011684:Purine Nucleosides / Q000737:chemistry*; D011741:Pyrimidine Nucleosides / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D011684:Purine Nucleosides; D011741:Pyrimidine Nucleosides; C002315:N(alpha)-acetyllysine; D008315:Malondialdehyde; D003849:Deoxyguanosine; D008239:Lysine