title: Conformational differences of the C8-deoxyguanosine adduct of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) within the NarI recognition sequence.
abstract: 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a highly mutagenic heterocyclic amine found in cooked meats. The major DNA adduct of IQ is at the C8-position of dGuo. We have previously reported the incorporation of the C8-IQ adduct into oligonucleotides, namely, the G1-position of codon 12 of the N-ras oncogene sequence (G1G2T) and the G3-position of the NarI recognition sequence (G1G2CG3CC) (Elmquist et al. (2004) J. Am. Chem. Soc. 126, 11189-11201). Ultraviolet spectroscopy and circular dichroism studies indicated that the conformation of the adduct in the two oligonucleotides was different, and they were assigned as groove-bound and base-displaced intercalated, respectively. The conformation of the latter was subsequently confirmed through NMR and restrained molecular dynamics studies (Wang et al. (2006) J. Am. Chem. Soc. 128, 10085-10095). We report here the incorporation of the C8-IQ adduct into the G1- and G2-positions of the NarI sequence. A complete analysis of the UV, CD, and NMR chemical shift data for the IQ protons are consistent with the IQ adduct adopting a minor groove-bound conformation at the G1- and G2-positions of the NarI sequence. To further correlate the spectroscopic data with the adduct conformation, the C8-aminofluorene (AF) adduct of dGuo was also incorporated into the NarI sequence; previous NMR studies demonstrated that the AF-modified oligonucleotides were in a sequence-dependent conformational exchange between major groove-bound and base-displaced intercalated conformations. The spectroscopic data for the IQ- and AF-modified oligonucleotides are compared. The sequence-dependent conformational preferences are likely to play a key role in the repair and mutagenicity of C8-arylamine adducts.
authors.affiliation: Departments of Chemistry and Biochemistry, Center in Molecular Toxicology, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235-1822, USA.
authors.forename: C Eric
authors.initials: CE
authors.lastname: Elmquist
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: James S
authors.initials: JS
authors.lastname: Stover
authors.forename: Michael P
authors.initials: MP
authors.lastname: Stone
authors.forename: Carmelo J
authors.initials: CJ
authors.lastname: Rizzo
mesh_terms: D001483:Base Sequence; D002273:Carcinogens / Q000737:chemistry*; D002942:Circular Dichroism; D004260:DNA Repair / Q000187:drug effects; D003849:Deoxyguanosine / Q000737:chemistry*; D019075:Electrophoresis, Capillary; D007364:Intercalating Agents; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry; D011804:Quinolines / Q000737:chemistry*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013056:Spectrophotometry, Ultraviolet
chemical_list: D002273:Carcinogens; D007364:Intercalating Agents; D009841:Oligonucleotides; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D003849:Deoxyguanosine