Abstract
In analogy with bleomycin, deglyco-bleomycin B2 has been found to form a stable, diamagnetic complex with Fe(II) and CO. Although the stoichiometry of this complex appeared to be the same as that formed with bleomycin, the geometry of the deglyco-bleomycin complex was fundamentally different, especially as regards orientation of the beta-aminoalanine moiety. In the presence of Fe(II) and O2, deglyco-bleomycin A2 and deglyco-bleomycin B2 were found to release [3H]thymine from radiolabeled PM-2 DNA; when employed at limiting concentrations, deglyco-bleomycin A2 and B2 gave about half as much [3H]thymine release as the respective bleomycins. In view of the spectral evidence (Burger, R. M., Horwitz, S. B., Peisach, J., and Wittenberg, J. B. (1979) J. Biol. Chem. 254, 12299-12302) that Fe(II) . bleomycin . CO has the same geometry as the complex formed by initial association of bleomycin, Fe(II), and O2, the accumulated data suggest strongly that all metal complexes of bleomycin (derivatives) capable of DNA degradation need not have the same geometry.
Highlights
In analogy with bleomycin, deglyco-bleomycinBzhas been found to forma stable, diamagnetic complexwith Few) and CO
The stoichiometry ofthis complex appearedto be the same as that formed with bleomycin, the geometry of the deglyco-bleomycin complex was fundamentally different,especially as regards orientation of the #?-aminoalanine moiety
We report on a derivative of bleomycin having two remarkable features, namely that (i) it effects [3H]thymine release from PM-2 DNA to anextent comparable to that of bleomycin itselfunder conditionslimitingfor antibiotic and (ii) it forms a stable, diamagnetic complex with Fe(I1) and CO, but one that is of fundamentally different geometry than the analogous complex formebdy bleomycin.As discussed these observations have important implicationsfor the design of bleomycin analogs
Summary
1979-1984. $jFellow of the Economic Development Administration of Puerto. ’absentia from Massachusetts Institute of Technology. The abbreviations used are: BLM, bleomycin; deglyco-BLMb, leomycin lacking the carbohydrate moiety. Required for DNA cleavage by BLMt,he structuresof metalbleomycin complexes are of considerable interest and have been studied intensively. These investigations have included x-ray crystallographic analysis of the Cu(I1)complex of P-3A [8], a biosynthetic intermediate structurally related to BLM, as well as numerous spectral studies of binary (see, e.g., Ref. 9) and ternary [10,11,12,13] complexes formedby bleomycins. We report on a derivative of bleomycin having two remarkable features, namely that (i) it effects [3H]thymine release from PM-2 DNA to anextent comparable to that of bleomycin itselfunder conditionslimitingfor antibiotic and (ii) it forms a stable, diamagnetic complex with Fe(I1) and CO, but one that is of fundamentally different geometry than the analogous complex formebdy bleomycin.As discussed these observations have important implicationsfor the design of bleomycin analogs
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