QM Calculations Revealed that Outer-Sphere Electron Transfer Boosted O-O Bond Cleavage in the Multiheme-Dependent...

The cytochrome bd oxygen reductase catalyzes the four-electron reduction of dioxygen to two water molecules. The structure of this enzyme reveals three heme molecules in the active site, which differs from that of heme-copper cytochrome c oxidase. The quantum chemical cluster approach was used to uncover the reaction mechanism of this intriguing metalloenzyme. The calculations suggested that a proton-coupled electron transfer reduction occurs first to generate a ferrous heme b₅₉₅. This is followed by the dioxygen binding at the heme d center coupled with an outer-sphere electron transfer from the ferrous heme b₅₉₅ to the dioxygen moiety, affording a ferric ion superoxide intermediate. A second proton-coupled electron transfer produces a heme d ferric hydroperoxide, which undergoes efficient O-O bond cleavage facilitated by an outer-sphere electron transfer from the ferrous heme b₅₉₅ to the O-O σ* orbital and an inner-sphere proton transfer from the heme d hydroxyl group to the leaving hydroxide. The synergistic benefits of the two types of hemes rationalize the highly efficient oxygen reduction repertoire for the multi-heme-dependent cytochrome bd oxygen reductase family.