Molecular mechanisms of binding and single-strand scission of DNA by the antitumor antibiotics saframycins A and C
| Autor: | Alummoottil V. Joshua, J. William Lown, Jeremy S. Lee |
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| Rok vydání: | 1982 |
| Předmět: | |
| Zdroj: | Biochemistry. 21:419-428 |
| ISSN: | 1520-4995 0006-2960 |
| Popis: | The quinone antitumor antibiotics saframycins A and C bind to duplex DNA and G,C containing complementary oligodeoxyribonucleotides at pHs below 5.5 via selective protonation of the antibiotics at the N-12 positions in an equilibrium process. This binding shows minor groove specificity to T4 DNA for both antibiotics. Saframycin A exhibits an additional mode of covalent binding to DNA, which is reversible by heating, via an animal linkage with the NH2 group of guanine. Covalent binding of saframycin A is enhanced by prior reduction of the quinone moiety via a different mechanism with concomitant elimination of the nitrile group and plausibly involves an intermediate quinone methide. Both saframycin A and saframycin C when reduced in situ with NADPH or sodium borohydride cause single-strand breaks, but not double-strand breaks, in PM2 covalently closer circular DNA. This latter reaction proceeds via intermediate semiquinones, the identity and conformation of which are established by EPR. The DNA scission process which requires oxygen is mediated by the generation of O2-., H2O2 and OH., the latter of which species was identified by spin trapping. The strand scission of DNA is pH dependent and, unlike the binding of the antibiotics, is strongly inhibited by Mg2+ and Zn2+ ions. |
| Databáze: | OpenAIRE |
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