GHK-Cu

GHK-Cu is the copper(II) complex of the tripeptide glycyl-L-histidyl-L-lysine, a sequence present in human plasma that binds copper with high affinity. In the PepXtide structural library the copper is shown chelated by the terminal amine, the backbone amide nitrogen and the histidine imidazole, with the metal relaxed to sit about 2 angstroms from each donor.

The uncomplexed GHK tripeptide is a distinct substance, C14H24N6O4 at 340.38 g/mol under CAS 49557-75-7. This listing is the copper complex.

The tripeptide was isolated from human serum by Pickart and Thaler and reported in Nature New Biology in 1973, with the sequence assigned in 1977. Its association with copper came seven years after the isolation, in a 1980 Nature paper reporting co-isolation with roughly equimolar copper and formation of a copper(II) complex. A related tripeptide motif occurs within the alpha-2 chain of type I collagen and within the protein SPARC, which has been proposed as a proteolytic origin for the circulating peptide.

The coordination geometry is well characterised and is what the structural model shows. In solution the complex is monomeric with three equatorial nitrogen donors: the glycine alpha-amino nitrogen, the deprotonated glycyl-histidyl amide nitrogen, and the histidine imidazole nitrogen. The fourth equatorial position is labile and is occupied by a carboxylate oxygen in the solid state but readily exchanges, forming ternary complexes with free amino acids such as histidine. The lysine side-chain amine takes no part in coordination at physiological pH, remaining protonated, and participates only under alkaline conditions. In the solid state the complex is dimeric.

No cell-surface receptor is established for this compound, and the molecular account is coordination chemistry and copper delivery rather than receptor pharmacology. One in-vitro result is unusually informative for distinguishing the complex from the free peptide: in human dermal fibroblast culture the complex raised matrix metalloproteinase-2 and the secretion of its tissue inhibitors TIMP-1 and TIMP-2, an effect reproduced by copper ions alone but not by copper-free tripeptide. Collagen-synthesis measurements in fibroblast culture report onset between picomolar and low picomolar concentrations with a maximum near one nanomolar. A widely cited broad gene-expression analysis should be read with its basis in mind: it profiled the peptide in only two cell lines.

Stability data are good for a metal complex. The compound is highly hydrophilic, with a distribution coefficient between about -2.4 and -2.5 across pH 4.5 to 7.4, and has been reported stable in water and in buffer over that pH range for at least two weeks at 60 degrees Celsius. It degrades under basic and oxidative stress by first-order kinetics, with three degradants resolved by HPLC-MS, one of them free histidine. Characterisation methods in the literature include single-crystal X-ray diffraction, electron paramagnetic resonance, X-ray absorption spectroscopy confirming copper(II) in a one-to-one complex, potentiometry and cyclic voltammetry, the last showing a copper(II) to copper(I) reduction accompanied by release of the metal.

One caution on specifications, because the public records genuinely conflict. Both one-to-one and two-to-one peptide-to-copper species are registered, with different formulae, different masses and different registry numbers, and charge states differ between records again. The figures published on this page are for the one-to-one complex under the registry number used for copper tripeptide-1. A certificate quoting a different stoichiometry is describing a different species, not a different measurement of this one.