Kumar Devesh, de Visser Samuël P, Shaik Sason
Department of Organic Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University, Jerusalem 91904, Israel.
J Am Chem Soc. 2005 Jun 8;127(22):8204-13. doi: 10.1021/ja0446956.
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. 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 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. The present contribution studies the stepwise and concerted acid-catalyzed mechanisms using H(3)O(+)(H(2)O)(n)(), n = 0-2. The effect of the acid strength is tested using the H(4)N(+)(H(2)O)(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 H(3)O(+)(H(2)O)(2) cluster. The calculated alpha-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.
该报告使用密度泛函理论，通过一个铁氢过氧化物络合物模型来研究血红素加氧酶（HO）降解血红素的机制。已知HO会捕获血红素分子并将其降解，以维持生物系统中的铁稳态。降解过程始于血红素的络合，然后形成铁-氢过氧物种，该物种随后通过羟基化作用氧化卟啉的中位，从而最终使卟啉环断裂。动力学同位素效应研究表明，该机制通过一系列水分子得到一般酸催化的辅助，且所有事件协同发生。然而，先前的理论处理表明，协同机制具有很高的势垒，远高于由铁-氢过氧化物的O-O键均裂引发的另一种机制。本研究使用H(3)O(+)(H(2)O)(n)（n = 0 - 2）研究了逐步和协同的酸催化机制。使用H(4)N(+)(H(2)O)(2)簇和完全质子化的铁氢过氧化物测试了酸强度的影响。所有计算表明，在速率决定步骤中涉及质子传递和O-O均裂的逐步机制比相应的完全协同机制具有低得多的势垒（>10千卡/摩尔）。对于H(3)O(+)(H(2)O)(2)簇，计算得到的溶剂动力学同位素效应与实验数据的最佳拟合。计算得到的α-氘二级动力学同位素效应是反向的（0.95 - 0.98），但远小于实验值（0.7）。讨论了这种定量差异的可能原因。提出了一些可能使实验能够区分逐步机制和协同机制的探针。
