%0 Journal Article
%A Kumar, Devesh
%A Hirao, Hajime
%A Shaik, Sason
%A Kozlowski, Pawel M.
%D 2006
%T Proton-Shuffle Mechanism of O−O Activation for Formation of
a High-Valent Oxo−Iron Species of Bleomycin
%U https://acs.figshare.com/articles/journal_contribution/Proton_Shuffle_Mechanism_of_O_O_Activation_for_Formation_of_a_High_Valent_Oxo_Iron_Species_of_Bleomycin/3040489
%R 10.1021/ja064611o.s001
%2 https://ndownloader.figshare.com/files/4743979
%K alternative
%K 2O
%K OH
%K bond
%K heterolytic cleavage
%K cytochrome c peroxidase
%K barrier
%K Cpd
%K BLM
%K DNA
%K DFT
%K ABLM
%K species
%K mechanism
%X 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−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).
%I ACS Publications