Peroxynitrite reaction products of 3′,5′-di-O-acetyl-8-oxo-7,8-dihydro-2′-deoxyguanosine

被引:78
作者
Niles, JC
Burney, S
Singh, SP
Wishnok, JS
Tannenbaum, SR
机构
[1] MIT, Div Bioengn & Environm Hlth, Cambridge, MA 02139 USA
[2] MIT, Dept Chem, Cambridge, MA 02139 USA
关键词
D O I
10.1073/pnas.96.21.11729
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Of the DNA bases, peroxynitrite (ONOO-) is most reactive toward 2'-deoxyguanosine (dGuo), but even more reactive with 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), requiring a 1,000-fold excess of dGuo to provide 50% protection against the reaction with 8-oxodGuo. Therefore, it seems reasonable that 8-oxodGuo is a potentially important target in DNA and that the structures of the reaction products with ONOO- should be characterized. Using 3'.5'-di-O-Ac-8-oxodGuo as a model compound, the reaction products with ONOO- have been isolated and identified under simulated physiological reaction conditions (phosphate/bicarbonate buffer at pH 7.2). The major reaction product, II, is unstable and undergoes base-mediated hydrolysis to 2,5-diaminoimidazol-4-one, IIa, and 3-(3,5-di-O-Ac-2-deoxy-beta-D-erythro-pentofuranosyl)-5-iminoimidazolidine-2,4-dione, IIb. The latter compound further hydrolyzes to 3-(3,5-di-O-Ac-2-deoxy-beta-D-erythro-pentofuranosyl)oxaluric acid, IIc. Other products include 3-(3,5-di-O-Ac-2-deoxy-beta-D-erythro-pentofuranosyl)-2,4,6-trioxo-[1,3,5]triazinane-1-carboxamidine, I, which further hydrolyzes to 1-(3,5-di-O-Ac-2-deoxy-beta-D-erythro-pentofuranosyl)cyanuric acid, la. 1-(3,5-di-O-Ac-2-deoxy-beta-D-erythro-pentofuranosyl)parabanic acid, III, is a minor product that also may contribute to formation of IIc. The major products formed in these reactions are biologically uncharacterized but are similar to modified DNA bases that have been shown to be both premutagenic and blocks to DNA polymerization.
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页码:11729 / 11734
页数:6
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