| Abstract
| - The report uses density functional theory to address the mechanism of heme degradation bythe enzyme heme oxygenase (HO) using a model ferric hydroperoxide complex. HO is known to trap hememolecules 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 formationof the iron−hydroperoxo species, which subsequently oxidizes the meso position of the porphyrin byhydroxylation, 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 thatall the events occur in concert. However, previous theoretical treatments indicated that the concertedmechanism has a high barrier, much higher than an alternative mechanism that is initiated by O−O bondhomolysis 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 theH4N+(H2O)2 cluster and a fully protonated ferric hydroperoxide. All the calculations show that a stepwisemechanism that involves proton relay and O−O homolysis, in the rate-determining step, has a much lowerbarrier (>10 kcal/mol) than the corresponding fully concerted mechanism. The best fit of the calculatedsolvent kinetic isotope effect, to the experimental data, is obtained for the H3O+(H2O)2 cluster. The calculatedα-deuterium secondary kinetic isotope effect is inverse (0.95−0.98), but much less so than the experimentalvalue (0.7). Possible reasons for this quantitative difference are discussed. Some probes are suggestedthat may enable experiment to distinguish the stepwise from the concerted mechanism.
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