Oxoferryl species in mononuclear non-heme iron enzymes: Biosynthesis, properties and reactivity from a theoretical perspective

Mononuclear non-heme iron enzymes perform a wide range of chemical reactions. Still, the catalytic mechanisms are usually remarkably similar, with formation of a key oxoferryl (Fe(IV)O) intermediate through two well-defined steps. First, two-electron reduction of dioxygen occurs to form a peroxo species, followed by OO bond cleavage. Even though the peroxo species have different chemical character in various enzyme families, the analogies between different enzymes in the group make it an excellent base for investigating factors that control metal–enzyme catalysis. We have used density-functional theory to model the complete chemical reaction mechanisms of several enzymes, e.g., for aromatic and aliphatic hydroxylation, chlorination, and oxidative ring-closure. Reactivity of the Fe(IV)O species is discussed with focus on electronic and steric factors determining the preferred reaction path. Various spin states are compared, as well as the two reaction channels that stem from involvement of different frontier molecular orbitals of Fe(IV)O. Further, the two distinctive species of Fe(IV)O, revealed by Mössbauer spectroscopy, and possibly relevant for specificity of aliphatic chlorination, can be identified. The stability of the modeling results have been analyzed using a range of approaches, from active-site models to multi-scale models that include classical free-energy contributions. Large effects from an explicit treatment of the protein matrix (∼10 kcal/mol) can be observed for O2 binding, electron-transfer and product release.

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► Theoretical modeling shows common strategies for biosynthesis of oxoferryl species.
► Transition states for electrophilic attack by 5[Fe(IV)O] in σ- and π-channels.
► The protein matrix affects the energy of Fe(II)OOH species by up to 17 kcal/mol.
► Results from different multi-scale models change by up to 9 kcal/mol.
► Discussion of how reaction modeling contributes to the understanding of enzymes.