Inherent stereospecificity in the reaction of aflatoxin B(1) 8,9-epoxide with deoxyguanosine and efficiency of DNA catalysis.
Kinetic analysis of guanine alkylation by aflatoxin B(1) exo-8,9-epoxide, the reactive form of the hepatocarcinogen aflatoxin B(1), shows the reaction to be >2000 times more efficient in DNA than in aqueous solution, that is, with free 2'-deoxyguanosine. Thermodynamic analysis reveals AFB(1) exo-8,9-epoxide intercalation as the predominant source of the observed DNA catalytic effect. However, the known exo > endo epoxide stereospecificity of the DNA alkylation is observed even with free deoxyguanosine (ratio >20:1 determined by LC-MS and NMR measurements), as predicted by theoretical calculations [ Bren , U. , et al. ( 2007 ) Chem. Res. Toxciol. 20 , 1134 - 1140 ].
Brown
Kyle L
KL
Department of Chemistry and Center in Molecular Toxicology, Vanderbilt University, Nashville, Tennessee 37232-0146, USA.
Bren
Urban
U
Stone
Michael P
MP
Guengerich
F Peter
FP
D016604:Aflatoxin B1 / Q000031:analogs & derivatives* / Q000737:chemistry; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry*; D003849:Deoxyguanosine / Q000737:chemistry*; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry; D013816:Thermodynamics
C006426:aflatoxin B1-2,3-oxide; D004247:DNA; D016604:Aflatoxin B1; D003849:Deoxyguanosine