Structures of exocyclic R,R - And S,S - N6, N 6-(2,3-dihydroxybutan-1,4-diyl)-2′-deoxyadenosine adducts induced by 1,2,3,4-diepoxybutane

Ewa A. Kowal, Uthpala Seneviratne, Susith Wickramaratne, Kathleen E. Doherty, Xiangkun Cao, Natalia Tretyakova, Michael P. Stone

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1,3-Butadiene (BD) is an industrial and environmental chemical present in urban air and cigarette smoke, and is classified as a human carcinogen. It is oxidized by cytochrome P450 to form 1,2,3,4-diepoxybutane (DEB); DEB bis-alkylates the N6 position of adenine in DNA. Two enantiomers of bis-N6-dA adducts of DEB have been identified: R,R-N 6,N6-(2,3-dihydroxybutan-1,4-diyl)-2′- deoxyadenosine (R,R-DHB-dA), and S,S-N6,N6-(2,3- dihydroxybutan-1,4-diyl)-2′-deoxyadenosine (S,S-DHB-dA) [ Seneviratne, U., Antsypovich, S., Dorr, D. Q., Dissanayake, T., Kotapati, S., and Tretyakova, N. (2010) Chem. Res. Toxicol. 23, 1556-1567 ]. Herein, the R,R-DHB-dA and S,S-DHB-dA adducts have been incorporated into the 5′-d(C 1G2G3A4C5X 6A7G8A9A10G 11)-3′:5′-d(C12T13T 14C15T16T17G18T 19C20C21G22)-3′ duplex [X 6 = R,R-DHB-dA (R6) or S,S-DHB-dA (S6)]. The structures of the duplexes were determined by molecular dynamics calculations, which were restrained by experimental distances obtained from NMR data. Both the R,R- and S,S-DHB-dA adducts are positioned in the major groove of DNA. In both instances, the bulky 3,4-dihydroxypyrrolidine rings are accommodated by an out-of-plane rotation about the C6-N6 bond of the bis-alkylated adenine. In both instances, the directionality of the dihydroxypyrrolidine ring is evidenced by the pattern of NOEs between the 3,4-dihydroxypyrrolidine protons and DNA. Also in both instances, the anti conformation of the glycosyl bond is maintained, which combined with the out-of-plane rotation about the C6-N 6 bond, allows the complementary thymine, T17, to remain stacked within the duplex, and form one hydrogen bond with the modified base, between the imine nitrogen of the modified base and the T17 N3H imino proton. The loss of the second Watson-Crick hydrogen bonding interaction at the lesion sites correlates with the lower thermal stabilities of the R,R- and S,S-DHB-dA duplexes, as compared to the corresponding unmodified duplex. The reduced base stacking at the adduct sites may also contribute to the thermal instability.

Original languageEnglish (US)
Pages (from-to)805-817
Number of pages13
JournalChemical research in toxicology
Issue number5
StatePublished - May 19 2014


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