Peroxide-induced hole hopping within heme peroxidases expands their substrate diversity and redox-signaling roles.

This focussed review provides the authors' perspective on how H2O2-induced, heme-mediated hole hopping in heme peroxidases expands their substrate diversity and hence physiological roles. First, the reported substrate diversity and functions of heme peroxidases are reviewed and an overview of hole hopping in oxidoreductases is provided. Following a concise introduction to peroxidase Compound I formation, regulation of hole donation to the polypeptide by residues surrounding the heme is considered. Studies from the literature of substrate oxidation by lactoperoxidase and lignin peroxidase are then briefly discussed with a focus on increased substrate diversity through hole hopping. Lastly, we recap our extensive mapping of hole hopping in yeast mitochondrial cytochrome c peroxidase (CCP) based largely on characterization of its oxidized proteoforms by mass spectrometry. Our unexpected findings on recombinant CCP and that isolated from yeast cells reveal how hole hopping unlocks unprecedented physiological functions for this heme peroxidase.