NMR characterization of a DNA duplex containing the major acrolein-derived deoxyguanosine adduct gamma -OH-1,-N2-propano-2'-deoxyguanosine.
The environmental and endogenous mutagen acrolein reacts with cellular DNA to produce several isomeric 1,N(2)-propanodeoxyguanosine adducts. High resolution NMR spectroscopy was used to establish the structural features of the major acrolein-derived adduct, gamma-OH-1,N(2)-propano-2'-deoxyguanosine. In aqueous solution, this adduct was shown to assume a ring-closed form. In contrast, when gamma-OH-1,N(2)-propano-2'-deoxyguanosine pairs with dC at the center of an 11-mer oligodeoxynucleotide duplex, the exocyclic ring opens, enabling the modified base to participate in a standard Watson-Crick base pairing alignment. Analysis of the duplex spectra reveals a regular right-handed helical structure with all residues adopting an anti orientation around the glycosidic torsion angle and Watson-Crick alignments for all base pairs. We conclude from this study that formation of duplex DNA triggers the hydrolytic conversion of gamma-OH-1,N(2)-propano-2'-deoxyguanosine to an open chain form, a structure that facilitates pairing with dC during DNA replication and accounts for the surprising lack of mutagenicity associated with this DNA adduct.
de los Santos
C
C
Department of Pharmacological Sciences, State University of New York at Stony Brook, New York 11794-8651, USA. cds@pharm.sunysb.edu
Zaliznyak
T
T
Johnson
F
F
D000171:Acrolein / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000737:chemistry*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011522:Protons
C424742:OH-1,-N(2)-propano-2'-deoxyguanosine; D011522:Protons; D000171:Acrolein; D004247:DNA; D003849:Deoxyguanosine