Our findings have significant biological significance, as they explain why the reduction plays an important role in activating LsAA9A, independently of the presence or absence of substrate. Rather, the substrate binding has a more subtle impact on the electronic structure, facilitating the reaction between LPMO and H2O2. From an electronic structure perspective, it could thus be more important to control the supply of reductant and H2O2 than the substrate supply in experimental settings, since substrate binding alone does not seem to activate LsAA9.