Tuning the Redox Properties of Copper(II) Complexes with Amyloid-β Peptides

Abstract

Copper complexes of metal binding domains of synthesized amyloid-β peptides -Aβ(1-16) and N-truncated Aβ(4-16) containing a novel N-terminal FRH sequence, as well as its shorter mutants were characterized by cyclic voltammetry. The influence of the peptide sequence and peptide to copper molar ratio on the electrochemical properties of the obtained structures were studied and discussed. The reversibility of the studied redox processes in copper complexes with Aβ(4-x) derivatives was also investigated. The results indicate the crucial role of Tyr10 in the redox process of the Aβ(4-x) complex, including the removal of reversibility of the Cu(II)/Cu(III) redox couple.

N‐Terminal Cu‐Binding Motifs (Xxx‐Zzz‐His, Xxx‐His) and Their Derivatives: Chemistry, Biology and Medicinal Applications

“…The reversibility is also dependent on the nature of the Xa nd Za nd of other amino-acid residues presentu pstream of the ATCUN motif. [2,22,34,36,38,39] Cu-XZH could not be electrochemically reduced down to À1.0 Vv s. NHE. [2] In contrast, Cu II -XH complexes cannotb eo xidized up to 1.2V vs. NHE, but can be reduced at ac athodic potential of about À0.2 Vv s. NHE.…”

“…[42] This agrees with most of the reported studies showingt hat Cu-XZH complex are not able to catalyze the oxidation of ascorbate efficiently.T his is confirmed by the measurementso ft he HOC productionb yC u II -XZH in the presence of ascorbate/O 2 ;compared to Cu II in buffer,orC u-peptide complexes like Cu II -Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] or Cu II -a-synuclein, the HOC production by Cu II -XZH was virtually absent. [2,22,39,41,[43][44][45] However,i ntroducing aH is-His motif nearby the ATCUN site can help Cu II -reduction by ascorbate, by coordination and stabilization of Cu I in the His-His motif. [46][47][48] Specifically, in the Nterminal peptideo ft he Ctr1 membrane copperr eceptor, containing an XZH motif followed by aH Hc ouple (MDHSHHMG…), the additiono fs toichiometric amounts of ascorbater esulted in ap artial reduction of the d-d band intensity.T his effect was assigned to the HH motif, which is able to bind Cu I ,a nd hence to stabilizei ta fter reduction.…”

Key Intermediate Species Reveal the Copper(II)‐Exchange Pathway in Biorelevant ATCUN/NTS Complexes

“…[13] More generally, it explains how some ATCUN/NTS complexes are redox active towards mild electron donors/acceptors, such as ascorbate/H 2 O 2 , despite the electrochemical studies reporting only the (often irreversible) Cu II /Cu III process at potentials around 0.8 V vs. Ag/AgCl, possibly too high to be physiologically relevant. [12,26] The ROS generation may be enabled by even minute amounts of the redox-active complex still present at physiological pH, as reported for example, for Cu 2+ aqua ion. [30] Therefore, the relative abundance of the 2N and 4N species under given conditions emerges as key factor in the redox activity of ATCUN/NTS complexes.…”

“…As expected, an irreversible oxidation peak attributed to a reactive Cu III species was detected at 0.774 AE 0.004 V (pH 5.0) and 0.798 AE 0.002 V (pH 7.4) (Figure S10). [7,12,26] The irreversibility of the Cu II /Cu III redox process can be explained by rapid oxygen-induced decarboxylation followed by hydroxylation at the carboxyl end of Cu IIcomplexed GGH, occuring via a Cu III intermediate. [27] The electrochemical behavior of Cu II /GGH at pH 7.4 confirms the predominance of the 4N complex indicated by equilibrium species distribution.…”

“…[10,11] The 4N Cu II complexes cannot be reduced electrochemically to the corresponding Cu I species. They can be oxidized to Cu III only at high potentials around 1 V, [3,11,12] but in an apparent contradiction with this fact, these 4N complexes were demonstrated recently to generate reactive oxygen species (ROS) under physiologically relevant conditions via an unidentified Cu I species. [13] These pieces of evidence, taken together, suggest the existence of distinct intermediate complex(es) responsible for kinetic and redox properties of nominally 4N ATCUN/NTS Cu II complexes.…”