Geometric and Electronic Structure/Function Correlations in Non-Heme Iron Enzymes

In recent years, significant progress has been made in understanding the geometric and electronic structures of the active sites of non-heme iron enzymes and the contributions of these sites to molecular mechanisms. Tables 1 and 2 present fairly complete lists of the presently known key classes of mononuclear and binuclear non-heme iron enzymes. As indicated in the tables, these enzymes participate in a range of reactions as extensive as those found in heme chemistry but are generally much less well understood. For most of the enzymes one of the reactants is dioxygen. The uncatalyzed reactions of O<sub>2</sub> with organic substrates are thermodynamically favorable but kinetically slow since they are spin forbidden and the one-electron reduction potential of O<sub>2</sub> is low. In the mononuclear non-heme iron enzymes, these reactions are catalyzed either by a high-spin ferrous site which is involved in dioxygen activation or by a high-spin ferric site which activates substrates. For some of the ferrous enzymes, an additional organic cofactor, α-ketoglutarate or pterin, participates in a coupled reaction with dioxygen where both the substrate and cosubstrate are oxygenated. Thus far, the only well-characterized oxygen intermediate is that for bleomycin, activated bleomycin, which is kinetically competent to cleave DNA in a hydrogen-atom abstraction reaction. In the binuclear non-heme iron enzymes, a diferrous site is involved in reversible O<sub>2</sub> binding to hemerythrin and O<sub>2</sub> activation in ribonucleotide reductase, methane monooxygenase, and Δ<sup>9</sup> desaturase. These show interesting structural differences which could contribute to differences in reactivity (vide infra). Hemerythrin has five histidine ligands, while methane monooxygenase, ribonucleotide reductase, and Δ<sup>9</sup> desaturase are rich in donor oxygen ligands. It had been thought that the strong donor ligation in the latter enzymes activates the sites for dioxygen reactivity; however, a series of membrane desaturases and monooxygenases has recently been determined to have binuclear iron sites which appear to be rich in histidine ligation. Dioxygen binding to hemerythrin involves transfer of two electrons and a proton to O<sub>2</sub> binding at a single iron center, and oxygen intermediates P, Q, and X (vide infra) have been observed in ribonucleotide reductase, Δ<sup>9</sup> desaturase, and methane monooxygenase. An oxygen intermediate has also been observed at the binuclear ferrooxidase site in ferritin, which appears to have structural and functional similarities to the binuclear iron site in rubrerythrin. Mononuclear non-heme iron sites are also involved in superoxide dismutation (SOD, Fe<sup>II</sup> and Fe<sup>III</sup>), hydrolysis (deformylase, Fe<sup>II</sup>), and hydration (nitrile hydratase, low-spin Fe<sup>III</sup>), and a binuclear non-heme iron center catalyzes phosphate ester hydrolysis (purple acid phosphatase, Fe<sup>III</sup>Fe<sup>II</sup>).

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