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Structures of Exocyclic R,R- and S,S-N(6),N(6)-(2,3-Dihydroxybutan-1,4-diyl)-2′-Deoxyadenosine Adducts Induced by 1,2,3,4-Diepoxybutane

[Image: see text] 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 N(6) position of adenine in DNA. Two enanti...

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Autores principales: Kowal, Ewa A., Seneviratne, Uthpala, Wickramaratne, Susith, Doherty, Kathleen E., Cao, Xiangkun, Tretyakova, Natalia, Stone, Michael P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027948/
https://www.ncbi.nlm.nih.gov/pubmed/24741991
http://dx.doi.org/10.1021/tx400472p
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author Kowal, Ewa A.
Seneviratne, Uthpala
Wickramaratne, Susith
Doherty, Kathleen E.
Cao, Xiangkun
Tretyakova, Natalia
Stone, Michael P.
author_facet Kowal, Ewa A.
Seneviratne, Uthpala
Wickramaratne, Susith
Doherty, Kathleen E.
Cao, Xiangkun
Tretyakova, Natalia
Stone, Michael P.
author_sort Kowal, Ewa A.
collection PubMed
description [Image: see text] 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 N(6) position of adenine in DNA. Two enantiomers of bis-N(6)-dA adducts of DEB have been identified: R,R-N(6),N(6)-(2,3-dihydroxybutan-1,4-diyl)-2′-deoxyadenosine (R,R-DHB-dA), and S,S-N(6),N(6)-(2,3-dihydroxybutan-1,4-diyl)-2′-deoxyadenosine (S,S-DHB-dA) [ U. Seneviratne, S. Antsypovich, D. Q. Dorr, T. Dissanayake, S. Kotapati, and N. Tretyakova (2010) Chem. Res. Toxicol.23, 1556−156720873715]. Herein, the R,R-DHB-dA and S,S-DHB-dA adducts have been incorporated into the 5′-d(C(1)G(2)G(3)A(4)C(5)X(6)A(7)G(8)A(9)A(10)G(11))-3′:5′-d(C(12)T(13)T(14)C(15)T(16)T(17)G(18)T(19)C(20)C(21)G(22))-3′ duplex [X(6) = R,R-DHB-dA (R(6)) or S,S-DHB-dA (S(6))]. 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-N(6) 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, T(17), 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 T(17) 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.
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spelling pubmed-40279482015-04-17 Structures of Exocyclic R,R- and S,S-N(6),N(6)-(2,3-Dihydroxybutan-1,4-diyl)-2′-Deoxyadenosine Adducts Induced by 1,2,3,4-Diepoxybutane Kowal, Ewa A. Seneviratne, Uthpala Wickramaratne, Susith Doherty, Kathleen E. Cao, Xiangkun Tretyakova, Natalia Stone, Michael P. Chem Res Toxicol [Image: see text] 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 N(6) position of adenine in DNA. Two enantiomers of bis-N(6)-dA adducts of DEB have been identified: R,R-N(6),N(6)-(2,3-dihydroxybutan-1,4-diyl)-2′-deoxyadenosine (R,R-DHB-dA), and S,S-N(6),N(6)-(2,3-dihydroxybutan-1,4-diyl)-2′-deoxyadenosine (S,S-DHB-dA) [ U. Seneviratne, S. Antsypovich, D. Q. Dorr, T. Dissanayake, S. Kotapati, and N. Tretyakova (2010) Chem. Res. Toxicol.23, 1556−156720873715]. Herein, the R,R-DHB-dA and S,S-DHB-dA adducts have been incorporated into the 5′-d(C(1)G(2)G(3)A(4)C(5)X(6)A(7)G(8)A(9)A(10)G(11))-3′:5′-d(C(12)T(13)T(14)C(15)T(16)T(17)G(18)T(19)C(20)C(21)G(22))-3′ duplex [X(6) = R,R-DHB-dA (R(6)) or S,S-DHB-dA (S(6))]. 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-N(6) 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, T(17), 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 T(17) 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. American Chemical Society 2014-04-17 2014-05-19 /pmc/articles/PMC4027948/ /pubmed/24741991 http://dx.doi.org/10.1021/tx400472p Text en Copyright © 2014 American Chemical Society
spellingShingle Kowal, Ewa A.
Seneviratne, Uthpala
Wickramaratne, Susith
Doherty, Kathleen E.
Cao, Xiangkun
Tretyakova, Natalia
Stone, Michael P.
Structures of Exocyclic R,R- and S,S-N(6),N(6)-(2,3-Dihydroxybutan-1,4-diyl)-2′-Deoxyadenosine Adducts Induced by 1,2,3,4-Diepoxybutane
title Structures of Exocyclic R,R- and S,S-N(6),N(6)-(2,3-Dihydroxybutan-1,4-diyl)-2′-Deoxyadenosine Adducts Induced by 1,2,3,4-Diepoxybutane
title_full Structures of Exocyclic R,R- and S,S-N(6),N(6)-(2,3-Dihydroxybutan-1,4-diyl)-2′-Deoxyadenosine Adducts Induced by 1,2,3,4-Diepoxybutane
title_fullStr Structures of Exocyclic R,R- and S,S-N(6),N(6)-(2,3-Dihydroxybutan-1,4-diyl)-2′-Deoxyadenosine Adducts Induced by 1,2,3,4-Diepoxybutane
title_full_unstemmed Structures of Exocyclic R,R- and S,S-N(6),N(6)-(2,3-Dihydroxybutan-1,4-diyl)-2′-Deoxyadenosine Adducts Induced by 1,2,3,4-Diepoxybutane
title_short Structures of Exocyclic R,R- and S,S-N(6),N(6)-(2,3-Dihydroxybutan-1,4-diyl)-2′-Deoxyadenosine Adducts Induced by 1,2,3,4-Diepoxybutane
title_sort structures of exocyclic r,r- and s,s-n(6),n(6)-(2,3-dihydroxybutan-1,4-diyl)-2′-deoxyadenosine adducts induced by 1,2,3,4-diepoxybutane
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027948/
https://www.ncbi.nlm.nih.gov/pubmed/24741991
http://dx.doi.org/10.1021/tx400472p
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