Density functional theory with the B3LYP hybrid functional has been used to study the mechanisms for dioxygen activation by four families of mononuclear non-heme iron enzymes: α-ketoacid-dependent dioxygenases, tetrahydrobiopterin-dependent hydroxylases, extradiol dioxygenases, and Rieske dioxygenases. These enzymes have a common active site with a ferrous ion coordinated to two histidines and one carboxylate group (aspartate or glutamate). In contrast to the heme case, this type of weak field environment always leads to a high-spin ground state. With the exception of the Rieske dioxygenases, which have an electron source outside the active site, the dioxygen activation process passes through the formation of a bridging-peroxide species, which then undergoes O–O bond cleavage finally leading to the four electron reduction of O2. In the case of tetrahydrobiopterin- and α-ketoacid-dependent enzymes, the O–O heterolysis yields a high-valent iron–oxo species, which is capable of performing a two-electron oxidation chemistry on various organic substrates. For the other two families of enzymes (extradiol dioxygenases and Rieske dioxygenases) the substrate oxidation and the O–O bond cleavage are found to be coupled. In the extradiol dioxygenases the product of the O–O bond cleavage is a ferric iron with an oxy-substrate with a mixture of radical and anionic character, which is essential for the selectivity of the catechol cleavage.
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