Proton-shuffle mechanism of O-O activation for formation of a high-valent oxo-iron species of bleomycin
Proton-shuffle mechanism of O-O activation for formation of a high-valent oxo-iron species of bleomycin
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DOI：
10.1021/ja064611o
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发表时间：
2006-12-20
影响因子：
15
通讯作者：
Kozlowski, Pawel M.
中科院分区：
文献类型：
--
作者：
Kumar, Devesh;Hirao, Hajime;Kozlowski, Pawel M.
博莱霉素（BLM）可在铁离子存在下利用H2 O2切割DNA。用密度泛函理论（DFT）研究了低自旋Fe-III-过氧化氢配合物BLM中O-O键断裂的机理。使用实际结构模型研究了以下备选假设：（a）O-O键的异裂，产生化合物I（Cpd I）样中间体，形式为BLM-Fe-V=O;（B）均裂O-O裂解，产生BLM-Fe-IV=O物质和OH。自由基;和（c）ABLM的直接O-O裂解/H-提取机制。计算表明，（a）是一种简单可行的机制;它涉及由BLM的侧链连接体介导的酸碱质子重排，从而导致O-O键的异裂断裂并产生Cpd I。发现化合物I的形成涉及13.3 kcal/mol的势垒，其低于具有31和17 kcal/mol的相应势垒的替代机制（B和c）中的势垒。如此形成的Cpd I物质在侧链接头上具有自由基，即戊酸甲酯（V），与BLM-Fe-IV=O复合物相邻，类似于血红素过氧化物酶中Poulos-Kraut质子-改组机制中细胞色素c过氧化物酶活性物质的形成（Poulos，T. L.的; Kraut，J.J.Biol.Chem.1980，255，8199-8205）。实验数据进行了讨论，并表明与此建议是雅阁。这表明BLM的高价态Cpd I类参与了DNA的切割。这是基于ABLM（Fe-III-OOH）的唯一反应性情景的替代机制假设。
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 Fe-III-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-V=O; (b) homolytic O-O cleavage, leading to a BLM-Fe-IV=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-Fe-IV=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 (Fe-III-OOH).