The effect of histidine, histamine, and imidazole on electrochemical properties of Cu() complexes of Aβ peptides containing His-2 and His-3 motifs

• Published in: Dalton transactions : an international journal of inorganic chemistry 2024-09, Vol.53 (36), p.15359-15371
• Main Authors: Tobolska, Aleksandra, Jab o ska, Agnieszka E, Suwi ska, Aleksandra, Wawrzyniak, Urszula E, Wróblewski, Wojciech, Wezynfeld, Nina E
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Binding sites; Electrochemical analysis; Histamine; Histidine; Imidazole; Nitrogen; Peptides; Rigid structures; Voltammetry
• ISSN: 1477-9226; 1477-9234; 1477-9234
• DOI: 10.1039/d4dt01354a

The N-truncation of amyloid beta (Aβ) peptides could lead to peptide sequences with the histidine residue at the second and third positions, creating His-2 and His-3 motifs, known as high-affinity Cu( ii ) binding sites. In such complexes, the Cu( ii ) ion is arrested in a rigid structure of a square-planar arrangement of nitrogen donors, which highly limits its susceptibility to Cu( ii ) reduction. Cu( ii ) reduction fuels the Cu( ii )/Cu( i ) redox cycle, which is engaged in the production of reactive oxygen species (ROS). Employing electrochemical techniques, cyclic voltammetry (CV) and differential pulse voltammetry (DPV), together with UV-vis spectroscopy, we showed that low-molecular-weight (LMW) substances, such as imidazole, histamine, and histidine, could enhance the redox activity of Cu( ii ) complexes of three models of N-truncated Aβ peptides, Aβ 4-9 , Aβ 5-9 , and Aβ 12-16 , identifying three main mechanisms. LMW compounds could effectively compete with Aβ peptides for Cu( ii ) ions, forming Cu( ii )/LMW species, which are more prone to Cu( ii ) reduction. LMW substances could also shift the equilibrium between the Cu( ii )/Aβ species towards the species with higher susceptibility to Cu( ii ) reduction. Finally, the presence of LMW molecules could promote Cu( i ) reoxidation in ternary Cu( ii )/Aβ/LMW systems. The obtained results raise further questions regarding the Cu( ii ) redox activity in Alzheimer's disease. Low molecular-weight substances may promote the Cu( ii )/Cu( i ) cycle for Cu( ii ) ions bound to N-truncated Aβ by (1) removing Cu( ii ) ions from Cu( ii )/Aβ complexes, (2) changing Cu( ii )/Aβ coordination, and (3) facilitating Cu( i ) reoxidation.