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.

Copper-Catalyzed Glutathione Oxidation is Accelerated by the Anticancer Thiosemicarbazone Dp44mT and Further Boosted at Lower pH

“…Interestingly, the importance of such partial decoordination on the reduction of Cu II by GSH was recently shown with the tridentate peptide ligand GHK. 25 It is also worth mentioning that the change in charge from the negative thiolate to a neutral thione is expected to decrease the electron density on Cu II and hence favor reduction to Cu I . Thus, considering that the Cu II −Dp44mT complex can exist in equilibrium with its protonated form Cu II −HDp44mT in solution (see Scheme 1), we have simulated the reprotonation of the N 2 atom (see Scheme 1) using the hydronium ion as a protonating agent.…”

Synthesis, Structure, and Biologic Activity of Some Copper, Nickel, Cobalt, and Zinc Complexes with 2‐Formylpyridine N4‐Allylthiosemicarbazone

“…The g//factor equals 2.20, while the hyperfine splitting equals 185 ± 5 10 −4 cm −1 (dotted lines). The parameters are in line with a equatorial donor set of [2N,S,O] [ 53 ] and strongly reminiscent with those of a Cu(II) complex bound to three nitrogen atoms and one thiolate ligand [ 54 ]. In the perpendicular region, super-hyperfine lines are observed that mirror the interaction of the Cu(II) center with nitrogen atoms form the ligand.…”

Copper-catalysed glutathione oxidation is accelerated by the anticancer thiosemicarbazone Dp44mT and further boosted at lower pH

“…Interestingly, the importance of such a partial de-coordination on the reduction of Cu II by GSH was recently shown with the tridentate peptide ligand GHK. 19 To this aim, considering that the Cu II -Dp44mT complex can exist in equilibrium with its protonated form Cu II -HDp44mT in solution (see Scheme 1), we have simulated the re-protonation of the N 2 atom (see Scheme 1) using a hydronium ion as a protonating agent. Thus, the reaction proceeds as shown in Scheme 2.…”