Theory favors a stepwise mechanism of porphyrin degradation by a ferric hydroperoxide model of the active species of heme oxygenase
Theory favors a stepwise mechanism of porphyrin degradation by a ferric hydroperoxide model of the active species of heme oxygenase
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DOI：
10.1021/ja0446956
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发表时间：
2005-06-08
影响因子：
15
通讯作者：
Shaik, S
中科院分区：
文献类型：
--
作者：
Kumar, D;de Visser, SP;Shaik, S
该报告使用密度泛函理论来解决血红素降解的血红素加氧酶（HO）使用模型铁氢过氧化物复合物的机制。已知HO捕获血红素分子并降解它们以维持生物系统中的铁稳态（Ortiz de蒙泰拉诺，P. R. 1998，31，543）。通过血红素的络合引发降解，然后形成铁-氢过氧物种，其随后通过羟基化氧化卟啉的中位，从而最终使卟啉环裂解。动力学同位素效应研究（Davydov，R.; Matsui，T.; Fujii，H.; Ikeda-Saito，M.;霍夫曼，B。M. J. Am. Soc.2003，125，16208）表明，该机制是由一般的酸催化作用通过水分子链辅助的，并且所有的事件都是一致发生的。然而，先前的理论处理表明，协同机制具有高势垒，远高于由铁-氢过氧化物的O-O键均裂引发的替代机制（Sharma，P.K.; Kevorkiants，R.; de Visser，S. P的; Kumar，D.; Shaik，S. Angew. Chem.Int.Ed.2004，43，1129）。本文研究了H3 O+（H2O）（n）（n = 0-2）的分步协同酸催化机理。使用H4 N+（H2O）（2）簇和完全质子化的过氧化氢铁测试酸强度的影响。所有的计算表明，一个逐步的机制，涉及质子中继和O-O均裂，在速率决定步骤，有一个低得多的势垒（> 10千卡/摩尔）比相应的完全协调机制。对H_3O+（H_2O）（2）团簇，计算的溶剂动力学同位素效应与实验数据拟合最好。计算的α-氘次级动力学同位素效应与实验值（0.95-0.98）相反，但远小于实验值（0.7）。这种定量差异的可能原因进行了讨论。一些探针的建议，可能使实验区分逐步从协同机制。
The report uses density functional theory to address the mechanism of heme degradation by the enzyme heme oxygenase (HO) using a model ferric hydroperoxide complex. HO is known to trap heme molecules and degrade them to maintain iron homeostasis in the biosystem (Ortiz de Montellano, P. R. Acc. Chem. Res. 1998, 31, 543). The degradation is initiated by complexation of the heme, then formation of the iron-hydroperoxo species, which subsequently oxidizes the meso position of the porphyrin by hydroxylation, thereby enabling eventually the cleavage of the porphyrin ring. Kinetic isotope effect studies (Davydov, R.; Matsui, T.; Fujii, H.; Ikeda-Saito, M.; Hoffman, B. M. J. Am. Chem. Soc. 2003, 125, 16208) indicate that the mechanism is assisted by general acid catalysis, via a chain of water molecules, and that all the events occur in concert. However, previous theoretical treatments indicated that the concerted mechanism has a high barrier, much higher than an alternative mechanism that is initiated by O-O bond homolysis of iron-hydroperoxide (Sharma, P. K.; Kevorkiants, R.; de Visser, S. P.; Kumar, D.; Shaik, S. Angew. Chem. Int. Ed. 2004, 43,1129). The present contribution studies the stepwise and concerted acid-catalyzed mechanisms using H3O+(H2O)(n), n = 0-2. The effect of the acid strength is tested using the H4N+(H2O)(2) cluster and a fully protonated ferric hydroperoxide. All the calculations show that a stepwise mechanism that involves proton relay and O-O homolysis, in the rate-determining step, has a much lower barrier (> 10 kcal/mol) than the corresponding fully concerted mechanism. The best fit of the calculated solvent kinetic isotope effect, to the experimental data, is obtained for the H3O+(H2O)(2) cluster. The calculated cc-deuterium secondary kinetic isotope effect is inverse (0.95-0.98), but much less so than the experimental value (0.7). Possible reasons for this quantitative difference are discussed. Some probes are suggested that may enable experiment to distinguish the stepwise from the concerted mechanism.