The second possibility (ii), i.e., formation of H 2 O 2 directly at the active-site, requires further reduction and transfer of two protons (see Fig. ). The most obvious proton donors are conserved residues in the second-coordination-sphere of copper. Caldararu et al. used a second-sphere glutamate as proton donor. Unfortunately, the sequence conservation is generally low across LPMO families, and even residues in the second-coordination-sphere of copper can vary considerably. This is especially apparent for the AA10 family, for which a recent analysis showed that approximately half of the cellulose-active AA10 LPMOs contain arginine, the glutamate used as proton donor in ref. 27, and phenylala-nine, whereas the other half contains histidine, glutamine and tyrosine. The latter motif is also significantly more prevalent across other LPMO families than AA10s. Thus, the question remains how transferrable the results by Caldararu et al. are to other LPMO families or to AA10 LPMOs that do not contain a secondcoordination-sphere glutamate functioning as proton donor. Experimental as well as computational studies have argued both for and against the use of a second-sphere histidine (HIS208 in Fig 1) as proton donor, and the role of this residue has been controversial. Notably, the investigations were preformed on an inhomogeneous set of LPMOs from different families and some focused on the substrate oxidation rather than the oxidase activity.