Conformations of adducts formed between the genotoxic benzo[a]pyrene-7,8-dione and nucleosides studied by density functional theory.
Benzo[a]pyrene (BP) is a widely distributed environmental pollutant that is metabolized by mammalian cells to a variety of genotoxic and carcinogenic intermediates that form covalent adducts with cellular DNA. One such pathway involves the metabolic activation of BP by members of the aldo-keto-reductase (AKR) family of enzymes to the highly reactive ortho-quinone, benzo[a]pyrene-7,8-dione (BPQ). This compound has been reported to react with the 2'-deoxynucleosides, dA and dG, under physiological conditions. Four BPQ-dG adducts and two -dA adducts were identified by mass spectrometry and NMR methods [Balu et al. (2004) Chem. Res. Toxicol. 17, 827-838]. However, the detailed conformations and absolute configurations around the linkage site have not been resolved. In order to determine the full conformations of these purine adducts, we carried out quantum mechanical geometry optimization using density functional theory. In the case of the BPQ-guanine adducts, six possible structures, each of which consists of two isomers, were identified. However, in the case of the adenine adducts, only four isomers were identified. The results suggest that stereoisomeric adduct pairs are expected to adopt opposite orientations with respect to the 5'-->3' direction of the modified DNA strands. The stereochemistry-dependent variations in adduct orientation may produce different biological effects, as has been observed in the case of DNA adducts derived from other metabolites of polycyclic aromatic hydrocarbons.
Lee
Hyun Mee
HM
Department of Chemistry, College of Sciences, Yeungnam University, Daedong, Gyeongsan City, Gyeong-buk 712-749, Republic of Korea.
Chae
Youn-Hee
YH
Kwon
Cheol
C
Kim
Seog K
SK
D001580:Benzopyrenes / Q000737:chemistry*; D003198:Computer Simulation; D018736:DNA Adducts / Q000737:chemistry*; D003853:Deoxyribonucleosides / Q000737:chemistry*; D006151:Guanosine / Q000737:chemistry; D008968:Molecular Conformation; D009699:N-Glycosyl Hydrolases / Q000737:chemistry; D009690:Nucleic Acid Conformation; D011789:Quantum Theory; D013237:Stereoisomerism
D001580:Benzopyrenes; D018736:DNA Adducts; D003853:Deoxyribonucleosides; D006151:Guanosine; C076588:benzo(a)pyrene-7,8-dione; D009699:N-Glycosyl Hydrolases; C019599:adenosine nucleosidase