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

Abstract

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-a-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.

Differences in and Comparison of the Catalytic Properties of Heme and Non‐Heme Enzymes with a Central Oxo–Iron Group

“…We used propene as a substrate since this is the smallest model in which competitive alkyl hydroxylation and C=C bond epoxidation mechanisms can be studied. [8,9] Received: October 31, 2005 Published online: February 10, 2006 . Keywords: density functional calculations · enzyme catalysis · enzyme models · epoxidation · hydroxylation…”

“…Earlier work on heme-type oxoiron porphyrin models for P450 and HRP systems showed that the regioselectivity of propene epoxidation versus methyl group hydroxylation is dependent on small environmental perturbations. [8,9] The electronic ground state of Cpd I of the heme enzymes P450 and HRP is a set of nearly degenerate quartet and doublet spin states, [10] which creates two-state reactivity patterns with competing reaction mechanisms on the two spin state surfaces. [11] In particular, the doublet spin state leads to product formation via a short-lived intermediate, whereas from the quartet spin state a long-lived intermediate is reached, which makes side-reactions leading to by-products possible.…”

Strengths, Weaknesses, Opportunities and Threats: Computational Studies of Mn- and Fe-Catalyzed Epoxidations

“…Interestingly, Shaik and co-workers further proposed that the preference for C− −C epoxidation shown by P450 CpdI in theoretical studies results from not accounting for the polarizing environment found in P450. Thus, a more refined model, including polarization effects, was developed, which accounted for the available experimental observations [95,96].…”

Chemistry and Applications of Iron–TAMLCatalysts in Green Oxidation Processes Based on Hydrogen Peroxide

“…The major structural difference between peroxidases and cytochrome P450s is that substrates can approach the heme iron only in the case of cytochrome P450. Therefore, the actual reaction between the oxidized Fe-TAML and a substrate may more closely mimic cytochrome P450 enzymes because in catalysis, peroxidase reactivity is limited by the access of the substrate to the oxidized iron [5,80,81]. At our present state of understanding, Fe-TAMLs are well described as being green oxidation catalysts.…”