Properties of Metallobleomycins Bound to DNA

Early studies of the interaction of ON-Fe(ii)Blm and OC-Fe(ii)Blm with DNA showed that DNA perturbs the metal site. The ESR signal of the former was dramatically changed by DNA, and the chemical shift of the NMR signal of the H2 proton of metal-bound imidazole in the latter was altered upon binding to DNA. - Furthermore, the low- to high-spin transition of Fe(m)Blm at pH 4, thought to result from protonation of the axial amine in the metal domain, was reversed upon addition of DNA, suggesting substantial interaction between DNA and the iron coordination site. Thus, it is evident that the metal domain chemistry of FeBlm is perturbed by the presence of DNA. 

What has become clear recently is that the alteration of metal domain properties upon binding to DNA occurs only when the structure interacts with specific 5 -GpPyrimidine-3 sites. Such evidence along with NMR structural results described below strongly link the metal domain structure with site specification that precedes the DNA damage reactions. 

In order to systematically investigate the roles that DNA may play in the chemistry of FeBlm bound to DNA, the properties of CoBlmDNA were first examined. The cobalt substitution was made because the dioxygen chemistries of Fe(ii) and Co(il) are similar, but the redox reactions of CoBlm are slower than those of FeBlm and are thus amenable to more detailed study. The pathway of reaction of Co(ii)Blm with O2 is analogous to that proposed for Fe(ii)Blm  

In this case, however, the presence of each species and the kinetics of reaction of each step can be observed, so that the detailed reaction mechanism above can be set forth. The products are analogous to those formed starting with Fe(ii)Blm. In contrast, they are stable and can be conveniently studied. 

The stabilization of dioxygenated Co(il)- and Fe(n)-Blm on DNA suggests that the complex is not able to undergo the rapid cycles of dissociation and rebinding necessary to find a partner to carry out Reactions 4 or 14. Nor is a rapid sliding process available to facilitate these reactions. 

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