Emerging structural and functional diversity in proteins with dioxygen-reactive dinuclear transition metal cofactors

Molecular oxygen is a powerful oxidant thermodynamically, but its triplet (S ¼ 1) electron-spin ground state imposes a high kinetic barrier for direct reaction with singlet (S ¼ 0) organic matter.¹ Upon partial reduction, however, more reactive species—superoxide, peroxide, and hydroxyl radical—are produced. In biology, the controlled, partial reduction of O₂ by an organic or transition metal enzyme cofactor is a versatile strategy to harness the potency of reduced oxygen species for useful chemical transformations. For metalloenzymes, the metal-oxygen adducts produced can be potent nucleophiles, electrophiles, or hydrogen-atom (H^%) abstractors. Collectively, these intermediates allow for transformation of even chemically inert centers of organic compounds present in the biosphere. In reductive activation of O₂, the first step, reduction to superoxide, is by far the least thermochemically favorable.¹ Enzymes with organic cofactors (e.g., flavins) can kinetically couple the initial uphill step with a second, favorable electron-transfer or radical-coupling step that generates a more stable (yet still potent) peroxide-level intermediate.² In enzymes that activate O₂ with transition metals, the appropriate combination of a metal ion (Mⁿ⁺) and ligands can make addition of O₂ more favorable, so that subsequent steps can then proceed efficiently from an accumulating (formally) M⁽ⁿ⁺¹⁾⁺–superoxide complex.¹ Heme-dependent oxygenases exemplify this strategy, forming a common, stable Fe^III-O₂⁻% adduct known as “compound 0” that undergoes rapid reduction by outer-sphere electron transfer.³ An alternative strategy for overcoming the unfavorable initial reduction step is approximation of two redox centers to enable concerted or coupled two-electron reduction of O₂ to peroxide-level complexes.