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The thermodynamics of Fe(III) to Fe(II) reduction for the high-spin and cyanide-bound form of a member of the animal heme peroxidase superfamily is reported. Major differences are found and discussed in relation to the unique catalytic properties of myeloperoxidase as well as physiological relevance.

In this work, we investigated the H2O2-induced oligomerization of wild-type human neuroglobin (hNgb) and of some selected variants (C46AC55A, Y44A, Y44F, Y44AC46AC55A, Y44AC46AC55A) to clarify how the process is affected by the Cys46/Cys55 disulfide bond and the distal H-bonding network and to figure out the molecular determinants of the H2O2-induced formation of amyloid type structures and hNgb aggregates. It turns out that hydrogen peroxide exerts a twofold effect on hNgb, inducing both heme breakdown and protein dimerization/polymerization. The enhanced resistance to the oxidizing effect of H2O2 of the disulfide free variants indicates that both effects are strictly influenced by the heme accessibility for H2O2. Most importantly, the H2O2-induced neuroglobin dimerization/polymerization turns out to be triggered by tyrosyl radicals resulting from the oxidizing action of Compound I ([Por•Fe(IV)=O]+). Peptide mapping indicates that the H2O2-induced dimerization/polymerization of hNgb mainly involves Tyr44, which forms covalent bonds with all the other tyrosine residues, with a minor contribution from Tyr88. The presented findings contribute further important pieces of information in the quest of identifying all capabilities of human neuroglobin and ultimately its physiological task., (Copyright 2024 The Author(s).)