Guanine alkylation by the potent carcinogen aflatoxin B1: quantum chemical calculations.
We report a series of ab initio and density functional theory simulations of guanine alkylation by aflatoxin B 1 exo-8,9-epoxide. This reaction represents an initial step of carcinogenesis associated with aflatoxin B 1, a potent genotoxic fungal metabolite. Effects of hydration were considered in the framework of the Langevin dipoles solvation model and the solvent reaction field method of Tomasi and co-workers. In silico-calculated activation free energies are in good agreement with the experimental value of 15.1 kcal/mol. This agreement presents strong evidence in favor of the validity of the proposed S(N)2 reaction mechanism and points to the applicability of quantum chemical methods in studies of reactions associated with carcinogenesis. In addition, we predict that the preference of aflatoxin B 1 exo-8,9-epoxide over the endo stereoisomer for the reaction with guanine exists in the aqueous solution and is only further amplified in the DNA duplex. Finally, through comparison with an analogous reaction between 3a,6a-dihydrofuro[2,3- b]furan exo-4,5-epoxide and guanine, we show that the large planar body of aflatoxin B 1 does not enhance its reactivity and related carcinogenicity. This explains why the planar region of related mycotoxins sterigmatocystin and aflatoxin G 1 could have been evolutionarily optimized in a different way.
Bren
Urban
U
National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia. bren@cmm.ki.si
Guengerich
F Peter
FP
Mavri
Janez
J
D016604:Aflatoxin B1 / Q000737:chemistry / Q000633:toxicity*; D000465:Algorithms; D000478:Alkylation; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity*; D004247:DNA / Q000737:chemistry; D004735:Energy Transfer; D004852:Epoxy Compounds / Q000737:chemistry; D006147:Guanine / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D011789:Quantum Theory
D002273:Carcinogens; D004852:Epoxy Compounds; D006147:Guanine; D004247:DNA; D016604:Aflatoxin B1