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Molecular basis for methoxyamine initiated mutagenesis. 1H nuclear magnetic resonance studies of base-modified oligodeoxynucleotides.
Stone, M J; Nedderman, A N; Williams, D H; Lin, P K; Brown, D M.
Afiliación
  • Stone MJ; University Chemical Laboratory Cambridge, U.K.
J Mol Biol ; 222(3): 711-23, 1991 Dec 05.
Article en En | MEDLINE | ID: mdl-1660932
In order to reach a more detailed understanding of the mechanism of the mutagenic action of methoxyamine and of N4-methoxycytidine and its 2'-deoxyribo-analogue, the solution structures of the self-complementary octanucleotide, d(CGAATTCG) and its analogues, d(CGAATCCG), d(CGAATMCG) and d(CGAATPCG) (designated 8mer-AT, 8mer-AC, 8mer-AM, and 8mer-AP, respectively), were investigated by 1H nuclear magnetic resonance spectroscopy; M is N4-methoxycytosine (mo4C) and P is an analogue, the bicyclic dihydropyrimido[4,5-c][1,2]oxazin-7-one, in which the N-O bond is held in the anti configuration with respect to N3 of the cytosine ring. Correlated spectroscopy and nuclear Overhauser spectroscopy allowed assignment of the base, anomeric and H2'/H2" protons in 8mers-AT, -AM and -AP, and showed that all three had features consistent with a regular B-DNA duplex structure. Duplex-to-coil transition temperatures were determined to be 52(+/- 2) degrees C (8mer-AT), 51(+/- 2) degrees C (8mer-AP), 32(+/- 2) degrees C (8mer-AM); on the chemical shift timescale, the melting transition was fast for 8mer-AT and 8mer-AP, but slow for 8mer-AM. Imino proton spectra were indicative of Watson-Crick base-pairing in 8mers-AT, -AP and -AM. The 8mer-AP duplex had a structure and melting characteristics virtually identical with those of the 8mer-AT duplex. The preferred syn configuration of the methoxyl group in M had a destabilising effect on the 8mer-AM duplex. At low temperatures, the A.M base-pair was in fast equilibrium between Watson-Crick and wobble configurations, with the methoxyl function anti-oriented, but the melting transition was accompanied by isomerization of the methoxyl group to the syn conformation. This syn-anti isomerization was the rate-determining step in the duplex-to-coil transition. The 8mer-AC oligomer did not form a stable duplex.
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Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Oligodesoxirribonucleótidos / Mutagénesis / Hidroxilaminas Tipo de estudio: Prognostic_studies Idioma: En Revista: J Mol Biol Año: 1991 Tipo del documento: Article
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Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Oligodesoxirribonucleótidos / Mutagénesis / Hidroxilaminas Tipo de estudio: Prognostic_studies Idioma: En Revista: J Mol Biol Año: 1991 Tipo del documento: Article