The intrinsic axial ligand effect on propene oxidation by horseradish peroxidase versus cytochrome P450 enzymes

The axial ligand effect on reactivity of heme enzymes is explored by means of density functional theoretical calculations of the oxidation reactions of propene by a model compound I species of horseradish peroxidase (HRP). The results are assessed vis-à-vis those of cytochrome P450 compound I. It is shown that the two enzymatic species perform C=C epoxidation and C-H hydroxylation in a multistate reactivity scenario with Fe^III and Fe^IV electromeric situations and two different spin states, doublet and quartet. However, while the HRP species preferentially keeps the iron in a low oxidation state (Fe^III), the cytochrome P450 species prefers the higher oxidation state (Fe^IV). It is found that HRP compound I has somewhat lower barriers than those obtained by the cytochrome P450 species. Furthermore, in agreement with experimental observations and studies on model systems, HRP prefers C=C epoxidation, whereas cytochrome P450 prefers C-H hydroxylation. Thus, had the compound I species of HRP been by itself, it would have been an epoxidizing agent, and at least as reactive as cytochrome P450. In the enzyme, HRP is much less reactive than cytochrome P450, presumably because HRP reactivity is limited by the access of the substrate to compound I.