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Proton-Shuffle Mechanism of O−O Activation for Formation of a High-Valent Oxo−Iron Species of Bleomycin

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journal contribution
posted on 20.12.2006 by Devesh Kumar, Hajime Hirao, Sason Shaik, Pawel M. Kozlowski
Bleomycins (BLMs) can utilize H2O2 to cleave DNA in the presence of ferric ions. DFT calculations were used to study the mechanism of O−O bond cleavage in the low-spin FeIII−hydroperoxo complex of BLM. The following alternative hypotheses were investigated using realistic structural models:  (a) heterolytic cleavage of the O−O bond, generating a Compound I (Cpd I) like intermediate, formally BLM−FeVO; (b) homolytic O−O cleavage, leading to a BLM−FeIVO species and an OH radical; and (c) a direct O−O cleavage/H-abstraction mechanism by ABLM. The calculations showed that (a) is a facile and viable mechanism; it involves acid−base proton reshuffle mediated by the side-chain linkers of BLM, causing thereby heterolytic cleavage of the O−O bond and generation of Cpd I. Formation of Cpd I is found to involve a barrier of 13.3 kcal/mol, which is lower than the barriers in the alternative mechanisms (b and c) that possess respective barriers of 31 and 17 kcal/mol. The so-formed Cpd I species with a radical on the side-chain linker, methylvalerate (V), adjacent to the BLM−FeIVO complex, resembles the formation of the active species of cytochrome c peroxidase in the Poulos−Kraut proton-shuffle mechanism in heme peroxidases (Poulos, T. L.; Kraut, J. J. Biol. Chem. 1980, 255, 8199−8205). Experimental data are discussed and shown to be in accord with this proposal. It suggests that the high-valence Cpd I species of BLM participates in the DNA cleavage. This is an alternative mechanistic hypothesis to the exclusive reactivity scenario based on ABLM (FeIII−OOH).

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