ja064611o_si_001.pdf (5.28 MB)
Proton-Shuffle Mechanism of O−O Activation for Formation of a High-Valent Oxo−Iron Species of Bleomycin
journal contribution
posted on 2006-12-20, 00:00 authored by Devesh Kumar, Hajime Hirao, Sason Shaik, Pawel M. KozlowskiBleomycins (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−FeVO; (b)
homolytic O−O cleavage, leading to a BLM−FeIVO 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−FeIVO 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).