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

The N-truncation of amyloid beta (Aß) 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 Aß peptides, Aß4-9, Aß5-9, and Aß12-16, identifying three main mechanisms. LMW compounds could effectively compete with Aß 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)/Aß 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)/Aß/LMW systems. The obtained results raise further questions regarding the Cu(II) redox activity in Alzheimer's disease.

The Angiotensin Metabolite His-Leu Is a Strong Copper Chelator Forming Highly Redox Active Species.

His-Leu is a hydrolytic byproduct of angiotensin metabolism, whose concentration in the bloodstream could be at least micromolar. This encouraged us to investigate its Cu(II) binding properties and the concomitant redox reactivity. The Cu(II) binding constants were derived from isothermal titration calorimetry and potentiometry, while identities and structures of complexes were obtained from ultraviolet-visible, circular dichroism, and room-temperature electronic paramagnetic resonance spectroscopies. Four types of Cu(II)/His-Leu complexes were detected. The histamine-like complexes prevail at low pH. At neutral and mildly alkaline pH and low Cu(II):His-Leu ratios, they are superseded by diglycine-like complexes involving the deprotonated peptide nitrogen. At His-Leu:Cu(II) ratios of ≥2, bis-complexes are formed instead. Above pH 10.5, a diglycine-like complex containing the equatorially coordinated hydroxyl group predominates at all ratios tested. Cu(II)/His-Leu complexes are also strongly redox active, as demonstrated by voltammetric studies and the ascorbate oxidation assay. Finally, numeric competition simulations with human serum albumin, glycyl-histydyl-lysine, and histidine revealed that His-Leu might be a part of the low-molecular weight Cu(II) pool in blood if its abundance is >10 µM. These results yield further questions, such as the biological relevance of ternary complexes containing His-Leu.

Dual mode of voltammetric studies on Cu(II) complexes of His2 peptides: phosphate and peptide sequence recognition.

Copper(II) complexes of peptides with a histidine residue at the second position (His2 peptides) provide a unique profile of electrochemical behavior, offering signals of both Cu(II) reduction and Cu(II) oxidation. Furthermore, their structures with vacant positions in the equatorial coordination plane could facilitate interactions with other biomolecules. In this work, we designed a library of His2 peptides based on the sequence of Aß5-9 (RHDSG), an amyloid beta peptide derivative. The changes in the Aß5-9 sequence highly affect the Cu(II) oxidation signals, altered further by anionic species. As a result, Cu(II) complexes of Arg1 peptides without Asp residues were chosen as the most promising peptide-based molecular receptors for phosphates. The voltammetric data on Cu(II) oxidation for binary Cu(II)-His2 peptide complexes and ternary Cu(II)-His2 peptide/phosphate systems were also tested for His2 peptide recognition. We achieved a highly promising identification of subtle modifications in the peptide sequence. Thus, we introduce voltammetric measurement as a potential novel tool for peptide sequence recognition.

Tuning the sumanene receptor structure towards the development of potentiometric sensors.

Herein, we report for the first time the application of a sumanene derivative in potentiometric recognition of caesium cations. The structure of the sumanene receptor was carefully tuned to obtain its compatibility with polyvinyl chloride plasticized membranes of potentiometric sensors. The developed ion-selective electrodes based on membranes doped with octyloxybenzene sumanene exhibited a near theoretical sensitivity towards caesium cations, with a detection limit of 4 µM Cs+.

Tuning Receptor Properties of Metal-Amyloid Beta Complexes. Studies on the Interaction between Ni(II)-Aß5-9 and Phosphates/Nucleotides.

Amyloid-beta (Aß) peptides, potentially relevant in the pathology of Alzheimer's disease, possess distinctive coordination properties, enabling an effective binding of transition-metal ions, with a preference for Cu(II). In this work, we found that a N-truncated Aß analogue bearing a His-2 motif, Aß5-9, forms a stable Ni(II) high-spin octahedral complex at a physiological pH of 7.4 with labile coordination sites and facilitates ternary interactions with phosphates and nucleotides. As the pH increased above 9, a spin transition from a high-spin to a low-spin square-planar Ni(II) complex was observed. Employing electrochemical techniques, we showed that interactions between the binary Ni(II)-Aß5-9 complex and phosphate species result in significant changes in the Ni(II) oxidation signal. Thus, the Ni(II)-Aß5-9 complex could potentially serve as a receptor in electrochemical biosensors for phosphate species. The obtained results could also be important for nickel toxicology.

Correction: Copper(II) complex of N-truncated amyloid-ß peptide bearing a His-2 motif as a potential receptor for phosphate anions.

Correction for 'Copper(ii) complex of N-truncated amyloid-ß peptide bearing a His-2 motif as a potential receptor for phosphate anions' by Aleksandra Tobolska et al., Dalton Trans., 2021, DOI: 10.1039/d0dt03898a.

Copper(ii) complex of N-truncated amyloid-ß peptide bearing a His-2 motif as a potential receptor for phosphate anions.

Electrochemical and spectroscopic studies demonstrated that the N-truncated amyloid ß peptide Aß5-9 (Arg-His-Asp-Ser-Gly-NH2) possessing histidine at position 2 (His-2) formed ternary complexes with copper(ii) and phosphate anions or phosphate groups of biomolecules. The recognition ability of Cu(ii)-Aß5-9 toward phosphate species provided a new perspective on designing phosphate-selective molecular receptors.

Aß5-x Peptides: N-Terminal Truncation Yields Tunable Cu(II) Complexes.

The Aß5-x peptides (x = 38, 40, 42) are minor Aß species in normal brains but elevated upon the application of inhibitors of Aß processing enzymes. They are interesting from the point of view of coordination chemistry for the presence of an Arg-His metal binding sequence at their N-terminus capable of forming a 3-nitrogen (3N) three-coordinate chelate system. Similar sequences in other bioactive peptides were shown to bind Cu(II) ions in biological systems. Therefore, we investigated Cu(II) complex formation and reactivity of a series of truncated Aß5-x peptide models comprising the metal binding site: Aß5-9, Aß5-12, Aß5-12Y10F, and Aß5-16. Using CD and UV-vis spectroscopies and potentiometry, we found that all peptides coordinated the Cu(II) ion with substantial affinities higher than 3 × 1012 M-1 at pH 7.4 for Aß5-9 and Aß5-12. This affinity was elevated 3-fold in Aß5-16 by the formation of the internal macrochelate with the fourth coordination site occupied by the imidazole nitrogen of the His13 or His14 residue. A much higher boost of affinity could be achieved in Aß5-9 and Aß5-12 by adding appropriate amounts of the external imidazole ligand. The 3N Cu-Aß5-x complexes could be irreversibly reduced to Cu(I) at about -0.6 V vs Ag/AgCl and oxidized to Cu(III) at about 1.2 V vs Ag/AgCl. The internal or external imidazole coordination to the 3N core resulted in a slight destabilization of the Cu(I) state and stabilization of the Cu(III) state. Taken together these results indicate that Aß5-x peptides, which bind Cu(II) ions much more strongly than Aß1-x peptides and only slightly weaker than Aß4-x peptides could interfere with Cu(II) handling by these peptides, adding to copper dyshomeostasis in Alzheimer brains.