Coordination and Metal Ion–Catalyzed Oxidation of a Mutated Prion Protein Fragment

Metal ion coordination and metal‐catalyzed oxidative processes play a key role in the pathology of neurodegenerative diseases involving prion protein peptide. In this work, the complex formation and copper(II)‐catalyzed oxidation of a prion protein–derived model peptide, H ₂ N‐GTHSAKHA‐NH ₂ , were investigated. Complex formation with Cu(II), Ni(II), and Zn(II) ions was studied by pH‐potentiometry, UV–vis, EPR, and circular dichroism spectroscopy. The results demonstrate the formation of mono‐ and dinuclear complexes, with a strong preference for albumin‐like N‐terminal coordination involving the amino group, deprotonated amide nitrogen atoms, and histidine imidazole donors. Copper(II) dominates at the N‐terminal site also in mixed‐metal systems, whereas nickel(II) and zinc(II) bind only to secondary C‐terminal sites. HPLC and LC–MS studies revealed that treatment with the Cu/H ₂ O ₂ system selectively oxidized the C‐terminal histidine residue, yielding 2‐oxo‐histidine. The effects of potential antioxidants on this oxidation process were also investigated. The addition of ascorbic acid significantly enhanced reactive oxygen species generation, resulting in increased peptide oxidation and DNA degradation, whereas the salan‐based Salpyran ligand inhibited oxidation.