10.1021/ja064611o.s001
Devesh Kumar
Devesh
Kumar
Hajime Hirao
Hajime
Hirao
Sason Shaik
Sason
Shaik
Pawel M. Kozlowski
Pawel M.
Kozlowski
Proton-Shuffle Mechanism of O−O Activation for Formation of
a High-Valent Oxo−Iron Species of Bleomycin
American Chemical Society
2006
alternative
2O
OH
bond
heterolytic cleavage
cytochrome c peroxidase
barrier
Cpd
BLM
DNA
DFT
ABLM
species
mechanism
2006-12-20 00:00:00
Journal contribution
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
Bleomycins (BLMs) can utilize H<sub>2</sub>O<sub>2</sub> 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 Fe<sup>III</sup>−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−Fe<sup>V</sup>O; (b)
homolytic O−O cleavage, leading to a BLM−Fe<sup>IV</sup>O species and an OH<sup>•</sup> 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 (<b>V</b>), adjacent to the BLM−Fe<sup>IV</sup>O complex, resembles the formation of
the active species of cytochrome <i>c</i> peroxidase in the Poulos−Kraut proton-shuffle mechanism in heme
peroxidases (Poulos, T. L.; Kraut, J. <i>J. Biol. Chem.</i> <b>1980</b>, <i>255</i>, 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 (Fe<sup>III</sup>−OOH).