EPR Spectroscopy of a Clinically Active (1:2) Copper(II)-Histidine Complex Used in the Treatment of Menkes Disease: A Fourier Transform Analysis of a Fluid CW-EPR Spectrum

Abstract

Redox active transition metal ions (e.g., iron and copper) have been implicated in the etiology of many oxidative stress-related diseases including also neurodegenerative disorders. Unbound copper can catalyze formation of reactive oxygen species (hydroxyl radicals) via Fenton reaction/Haber-Weiss chemistry and therefore, under physiological conditions, free copper is potentially toxic and very rarely exists inside cells. Copper(II) bound to the aminoacid L-histidine represents a species discovered in blood in the mid 60s and since then extensive research on this complex was carried out. Copper bound to L-histidine represents an exchangeable pool of copper(II) in equilibrium with the most abundant blood plasma protein, human serum albumin. The structure of this complex, in aqueous solution, has been a subject of many studies and reviews, however without convincing success. The significance of the (1:2) copper(II)-L-histidine complex at physiological pH documents its therapeutic applications in the treatment of Menkes disease and more recently in the treatment of infantile hypertrophic cardioencephalomyopathy. While recently the (1:2) Cu(II)-L-His complex has been successfully crystallized and the crystal structure was solved by X-ray diffraction, the structure of the complex in fluid solution at physiological OPEN ACCESSMolecules 2014, 19 981 pH is not satisfactorily known. The aim of this paper is to study the (1:2) Cu(II)-L-histidine complex at low temperatures by X-band and S-band EPR spectroscopy and at physiological pH at room temperature by Fourier transform CW-EPR spectroscopy.

Aggregation of Microtubule Binding Repeats of Tau Protein is Promoted by Cu2+

“…A number of Cu-peptides have been structurally characterized allowing a detailed analysis of the Cu-coordination environment. 51−54 The EPR results further support the coordination of the imidazole ring of His to Cu 2+ , as indicated in Figure 3C. The involvement of the peptide backbone in coordination to Cu 2+ is well known and a number of structurally well-characterized examples have been reported in the literature.…”

mtDNA depletion‐like syndrome in Wilson disease

“…More detailed information on each of the modules is found in Dataset S1 was presented roughly as having half-Lorentzian and half-Gaussian broadenings with a g value of 2.16. The signal matched the signal observed with a standard solution of Cu(I)-cysteine at acidic pH ( Figure S5B), 33 fitting the spectrum of copper sulphate at acidic pH (3 N HCl). This signal was characterized by a copper-chloride/ water complex in fast dynamics and/or coupled by exchange and magnetic dipolar interaction with spectroscopic parameters consistent with data reported for Cu(II).…”

Truncated Amyloid-β(11–40/42) from Alzheimer Disease Binds Cu2+ with a Femtomolar Affinity and Influences Fiber Assembly

“…The tight affinity of Cu 2ϩ for A␤ requires a highly soluble competitor so glycine and histidine were chosen for their relatively high solubility. Glycine has a micromolar affinity for Cu 2ϩ and forms a bidentate complex via its amino and carboxylate groups, whereas histidine has a nanomolar affinity and can coordinate Cu 2ϩ , forming a Cu 2ϩ (His) 2 bidentate complex at physiological pH (60).…”