The oxidation of inactive C-H bonds requires a potent oxidant; several theoretical studies have shown that a Cu(II)-oxyl is sufficiently potent. This Cu(II)-oxyl can be formed with a suitable co-substrate after reduction of the Cu(II)-resting state (see Fig. , structure 1). Whether this co-substrate is O 2 or H 2 O 2 is still an ongoing debate, although some LPMOs have been shown to use exclusively hydrogen peroxide. While a major focus in LPMO research has been the investigation of the substrate oxidation mechanism, the potent oxidative species can also cause oxidative damage to LPMOs in the absence of a substrate. This self-oxidation remains poorly understood but renders LPMOs inactive and thus hinders efficient exploitation of the enzymes. Proteomics Figure : a) Formation of Cu(II)-oxyl 1 from the Cu(II)-resting state (in gray) from a reductant and hydrogen peroxide, and generation of intermediates 2 and 3 from 1. Intermediates 1-3 (in black) are investigated here for their role as part of oxidative damage or protective pathways (species in gray are not included in this study). b) Ball-and-stick model of the first coordination sphere of the QM/MM optimized Cu(II)-resting state of LsAA9 employing TPSS/def2-SV(P).