How Oxygen Binding Enhances Long-Range Electron Transfer: Lessons From Reduction of Lytic Polysaccharide...

Long-range electron transfer (ET) in metalloenzymes is a general and fundamental process governing O₂ activation and reduction. Lytic polysaccharide monooxygenases (LPMOs) are key enzymes for the oxidative cleavage of insoluble polysaccharides, but their reduction mechanism by cellobiose dehydrogenase (CDH), one of the most commonly used enzymatic electron donors, via long-range ET is still an enigma. Using multiscale simulations, we reveal that interprotein ET between CDH and LPMO is mediated by the heme propionates of CDH and solvent waters. We also show that oxygen binding to the copper center of LPMO is coupled with the long-range interprotein ET. This process, which is spin-regulated and enhanced by the presence of O₂ , directly leads to LPMO-Cu^II -O₂^- , bypassing the formation of the generally assumed LPMO-Cu^I species. The uncovered ET mechanism rationalizes experimental observations and might have far-reaching implications for LPMO catalysis as well as the O₂ - or CO-binding-enhanced long-range ET processes in other metalloenzymes.