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Intermediate Cu(II)-Thiolate Species in the Reduction of Cu(II)GHK by Glutathione: A Handy Chelate for Biological Cu(II) Reduction.

ABSTRACT: Gly-His-Lys (GHK) is a tripeptide present in the human bloodstream that exhibits a number of biological functions. Its activity is attributed to the copper-complexed form, Cu(II)GHK. Little is known, however, about the molecular aspects of the mechanism of its action. Here, we examined the reaction of Cu(II)GHK with reduced glutathione (GSH), which is the strongest reductant naturally occurring in human plasma. Spectroscopic techniques (UV-vis, CD, EPR, and NMR) and cyclic voltammetry helped unravel the reaction mechanism. The impact of temperature, GSH concentration, oxygen access, and the presence of ternary ligands on the reaction were explored. The transient GSH-Cu(II)GHK complex was found to be an important reaction intermediate. The kinetic and redox properties of this complex, including tuning of the reduction rate by ternary ligands, suggest that it may provide a missing link in copper trafficking as a precursor of Cu(I) ions, for example, for their acquisition by the CTR1 cellular copper transporter.

SUBMITTER: Ufnalska I

PROVIDER: S-EPMC8653159 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Ternary Cu(II) Complex with GHK Peptide and Cis-Urocanic Acid as a Potential Physiologically Functional Copper Chelate.

Project description:The tripeptide NH2-Gly-His-Lys-COOH (GHK), cis-urocanic acid (cis-UCA) and Cu(II) ions are physiological constituents of the human body and they co-occur (e.g., in the skin and the plasma). While GHK is known as Cu(II)-binding molecule, we found that urocanic acid also coordinates Cu(II) ions. Furthermore, both ligands create ternary Cu(II) complex being probably physiologically functional species. Regarding the natural concentrations of the studied molecules in some human tissues, together with the affinities reported here, we conclude that the ternary complex [GHK][Cu(II)][cis-urocanic acid] may be partly responsible for biological effects of GHK and urocanic acid described in the literature.

| S-EPMC7503498 | biostudies-literature

The tri-peptide GHK-Cu complex ameliorates lipopolysaccharide-induced acute lung injury in mice.

Project description:The tripeptide-copper complex glycyl-l-histidyl-l-lysine-Cu (II) (GHK-Cu) is involved in wound healing and tissue remodeling. Although GHK-Cu exhibits anti-aging and tissue renewing properties, its roles in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are still unknown. Therefore, we examined the effects of GHK-Cu in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages in vitro and ALI in mice in vivo. GHK-Cu treatment reduced reactive oxygen species (ROS) production, increased superoxide dismutase (SOD) activity while decreased TNF-? and IL-6 production through the suppression of NF-?B p65 and p38 MAPK signaling in vitro and in vivo model of ALI. Moreover, GHK-Cu attenuated LPS-induced lung histological alterations, suppressed the infiltration of inflammatory cells into the lung parenchyma in LPS-induced ALI in mice. Taken together, these findings demonstrate that GHK-Cu possesses a protective effect in LPS-induced ALI by inhibiting excessive inflammatory responses; accordingly it may represent a novel therapeutic approach for ALI/ARDS.

| S-EPMC5295439 | biostudies-literature

Tetranuclear Cu(ii)-chiral complexes: synthesis, characterization and biological activity.

Project description:Tetranuclear chiral Cu(ii)-Schiff-base complexes S-1 and R-1, were synthesised using enantiomerically pure (S)-(H2vanPheol) and (R)-(H2vanPheol) ligands respectively in the ratio of 1 : 1 of Cu(NO3)2 to (S/R)-(H2vanPheol) in MeOH at room temperature. A pair of polynuclear chiral Cu(ii)-cluster complexes were characterized using single-crystal X-ray diffraction, elemental analysis, infrared and CD spectroscopy. The results revealed the importance of these chiral ligands encouraging the arrangement of copper metal in non-centrosymmetric polar packing. The potential of the novel [Cu4(S/R-vanPheol)2(S/R-HvanPheol)2(CH3OH)2](NO3)2 complexes as biologically active compounds was assessed in particular regarding their anti-proliferative and anti-microbial properties.

| S-EPMC9069531 | biostudies-literature

Cationic Peptides and Their Cu(II) and Ni(II) Complexes: Coordination and Biological Characteristics.

Project description:Antimicrobial peptides are a promising group of compounds used for the treatment of infections. In some cases, metal ions are essential to activate these molecules. Examples of metalloantibiotics are, for instance, bleomycin and dermcidin. This study is focused on three new pseudopeptides with potential biological activity. The coordination behavior of all ligands with Cu(II) and Ni(II) ions has been examined. Various analytical methods such as potentiometric titration, UV-Vis and CD spectroscopies, and mass spectrometry were used. All compounds are convenient chelators for metal ion-binding. Two of the ligands tested have histidine residues. Surprisingly, imidazole nitrogen is not involved in the coordination of the metal ion. The N-terminal amino group, Dab side chains, and amide nitrogen atoms of the peptide bonds coordinated Cu(II) and Ni(II) in all the complexes formed. The cytotoxicity of three pseudopeptides and their complexes was evaluated. Moreover, their other model allowed for assessing the attenuation of LPS-induced cytotoxicity and anti-inflammatory activities were also evaluated, the results of which revealed to be very promising.

| S-EPMC8584440 | biostudies-literature

Spectroscopic Investigations of Catalase Compound II: Characterization of an Iron(IV) Hydroxide Intermediate in a Non-thiolate-Ligated Heme Enzyme.

Project description:We report on the protonation state of Helicobacter pylori catalase compound II. UV/visible, Mössbauer, and X-ray absorption spectroscopies have been used to examine the intermediate from pH 5 to 14. We have determined that HPC-II exists in an iron(IV) hydroxide state up to pH 11. Above this pH, the iron(IV) hydroxide complex transitions to a new species (pKa = 13.1) with Mössbauer parameters that are indicative of an iron(IV)-oxo intermediate. Recently, we discussed a role for an elevated compound II pKa in diminishing the compound I reduction potential. This has the effect of shifting the thermodynamic landscape toward the two-electron chemistry that is critical for catalase function. In catalase, a diminished potential would increase the selectivity for peroxide disproportionation over off-pathway one-electron chemistry, reducing the buildup of the inactive compound II state and reducing the need for energetically expensive electron donor molecules.

| S-EPMC5987761 | biostudies-literature

In Vitro and in Vivo Studies of pH-Sensitive GHK-Cu-Incorporated Polyaspartic and Polyacrylic Acid Superabsorbent Polymer.

Project description:The main aim of this study was to evaluate the in vitro and in vivo efficiency of the polyaspartic acid- and acrylic acid-based superabsorbent polymer. The synthesized polymer was first investigated to check the blood compatibility by protein adsorption and blood clotting tests. Further, the GHK-Cu peptide was incorporated within the polymer and release studies were performed to evaluate the drug-delivery efficiency of the superabsorbent polymer. The polymer with best peptide release results were further used for in vivo analysis for wound healing. The healing efficiency of polymer with and without peptide was analyzed using wound closure, biochemical assay, histopathological, and toxicity studies.

| S-EPMC6893953 | biostudies-literature

Interaction between glutathione and Cu(II) in the vicinity of nucleic acids.

Project description:GSH interacts with Cu(II) in the vicinity of DNA (pH approximately 7) to form the DNA-Cu(I) complex, which can be quantified by characteristic absorption changes [e.g. delta epsilon 295 = 4516 cm-1.M-1 Cu(I)]. Under initial conditions of Cu(II)/GSH >> 1 and DNA(base)/Cu(II) >> 5, the stoichiometry is 1 DNA-Cu(I) per SH group (also for other thiols). Stopped-flow kinetics show that the complex is formed with half-lives of 1-30 s, depending on the environment, but independent of O2. DNA-Cu(I) generation is much slower, less efficient, and O2-dependent at Cu(II)/GSH < 1, or when GSH interacts with Cu(II) before the addition of DNA. Interaction of GSH with Cu(II) in the presence of DNA [at Cu(II)/GSH > 1] leads to DNA-associated transients, probably DNA-GS(-)-Cu(I); DNA-Cu(I) formation under these conditions is proposed to occur by ligand exchange: DNA-GS(-)-Cu(I)+Cu(II)<-->DNA-Cu(I)+GS(-)-Cu(II). There is no evidence for generation of free thiyl radicals (GS.) on reaction of Cu(II) with GSH. Formation of DNA-Cu(I) is, in our opinion, a primary step involved in DNA-strand cleavage by GSH in the presence of Cu(II) [Reed and Douglas (1991) Biochem. J. 275, 601-608]. In this context the question of the pro-oxidative and/or antioxidative activity of GSH, when combined with copper, is discussed. GSH also generates Cu(I) complexes with other nucleic acids. An updated order of affinities of various nucleic acids for Cu(I) is presented. Cu(I) exhibits a high preference for alternating dG-dC sequences and might even be a Z-DNA inducer. The poly(C)-Cu(I) complex seems to form a base-paired structure at pH approximately 7, as demonstrated by intercalation of ethidium bromide.

| S-EPMC1137238 | biostudies-other

Spectroscopic Characterization, Cyclic Voltammetry, Biological Investigations, MOE, and Gaussian Calculations of VO(II), Cu(II), and Cd(II) Heteroleptic Complexes.

Project description:A novel hydrazone ligand (o-H2BMP) N-(benzo[d]thiazol-2-yl)-3-oxo-3-(2-(1-(pyridin-2-yl)ethylidene)hydrazinyl)propanamide alongside its Cu(II), Cd(II), and VO(II) complexes were prepared and structurally characterized via various spectroscopic analyses (Fourier transform infrared spectroscopy, UV-visible spectroscopy, 1H/13C NMR spectroscopy, liquid chromatography coupled to mass spectrometry, and electron paramagnetic resonance spectroscopy) as well as by elemental analysis, thermal gravimetry analysis/differential thermal analysis, and magnetic moment measurements. Powder X-ray diffraction analysis was also performed for the free ligand and its metal complexes to determine the crystallographic structures and atomic spacing. It also provided information on unit cell dimensions and the average crystallite size. Furthermore, geometric optimization and computational studies were carried out by applying Gaussian (09) software based on density-functional theory coupled with the B3LYP functional and LANL2DZ/6-31+G(d,p) mixed basis set to evaluate some distinct features such as molecular electrostatic potential, E HOMO, and E LUMO. Moreover, electrochemical measurements were performed for Cu(II) in the absence/presence of the chelating agent to predict the effect of complexation interaction in the solution state study. As part of the biological examination, antioxidant and antimicrobial assays were conducted for each compound individually, in addition to cytotoxicity evaluations via MTT assays for all isolated complexes compared to the corresponding metal salts. The MOE (molecular operating environment) approach was also applied to model the interface between the isolated compounds and proteins that were expressed in breast cancer at the atomic level.

| S-EPMC10116629 | biostudies-literature

Chemical cleavage of plasmid DNA by glutathione in the presence of Cu(II) ions. The Cu(II)-thiol system for DNA strand scission.

Project description:In the presence of Cu(II) ions, supercoiled DNA is cleaved in neutral solution by low concentrations of thiols. Supercoiled plasmid DNA is cleaved first to open circular DNA, which in turn produces linear DNA and eventually fragments. Cleavage is strongly temperature-dependent and is maximal at 0.10-0.25 M-NaCl concentration. In the presence of excess of either component of the Cu(II)-thiol pair, the extent of cleavage depended on the concentration of the limiting partner, and was easily detectable down to micromolar concentrations of limiting GSH. Scavengers of oxygen-derived species (such as hydrogen peroxide, superoxide radical ion and hydroxyl radical) indicated that the hydroxyl radical may be involved in the cleavage mechanism. DNA cleavage leads to some production of 2-thiobarbituric acid-reactive species and some of the cleavage sites, at least, had 5'-hydroxy and/or 3'-hydroxy groups. There was extensive base damage before cleavage. Studies with S1 nuclease indicated no gross sequence preference for Cu(II)-GSH cleavage of pSP64 plasmid DNA. The Cu(II)-thiol system did not appear to target special structural features in the DNA such as Z-DNA inserts, cruciform structures or left-handed (but non-Z) DNA. Cleavage might arise from a reagent generated either by the Cu(II)-thiol combination in free solution or by attack involving Cu(II) ions pre-bound to DNA. The attack of GSH plus Cu(II) ions on DNA may be a potential toxic lesion under physiological conditions unless special protective measures operate efficiently in the cell.

| S-EPMC1150097 | biostudies-other

Tuning the Reactivity of Radical through a Triplet Diradical Cu(II) Intermediate in Radical Oxidative Cross-Coupling.

Project description:Highly selective radical/radical cross-coupling is paid more attention in bond formations. However, due to their intrinsic active properties, radical species are apt to achieve homo-coupling instead of cross-coupling, which makes the selective cross-coupling as a great challenge and almost untouched. Herein a notable strategy to accomplish direct radical/radical oxidative cross-coupling has been demonstrated, that is metal tuning a transient radical to a persistent radical intermediate followed by coupling with another transient radical. Here, a transient nitrogen-centered radical is tuned to a persistent radical complex by copper catalyst, followed by coupling with a transient allylic carbon-centered radical. Firstly, nitrogen-centered radical generated from N-methoxybenzamide stabilized by copper catalyst was successfully observed by EPR. Then DFT calculations revealed that a triplet diradical Cu(II) complex formed from the chelation N-methoxybenzamide nitrogen-centered radical to Cu(II) is a persistent radical species. Moreover, conceivable nitrogen-centered radical Cu(II) complex was observed by high-resolution electrospray ionization mass spectrometry (ESI-MS). Ultimately, various allylic amides derivatives were obtained in good yields by adopting this strategy, which might inspire a novel and promising landscape in radical chemistry.

| S-EPMC4630646 | biostudies-literature

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