The plasma tripeptide glycyl-L-histidyl-L-lysine (GHL), when added at nanomolar concentrations to a wide group of cultured systems, produces a disparate set of responses ranging from the stimulation of growth and differentiation to outright toxicity1–3. Such diverse actions imply that this tripeptide mediates some basic biochemical function common to many types of cells and organisms. During the isolation of GHL we found the compound to co-isolate through a number of steps with approximately equimolar copper and about 1/5 molar iron1. Maximal effects on hepatoma cells (HTC4) were seen when the peptide was added with copper and iron to the growth medium1. Structure–function studies revealed that several tripeptides with a histidyl-lysyl linkage were nearly as active as GHL1. The association of GHL with copper and a homology similarity between the tripeptide and the copper transport sites on albumin and α-fetoprotein, where the cupric atom is bound to a histidyl residue adjacent to a basic residue, suggested that GHL may act as a copper transport factor4. We report here that the tripeptide readily forms complexes with copper(II) and enhances the uptake of the metal into cultured hepatoma cells.
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Pickart, L., Freedman, J., Loker, W. et al. Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells. Nature 288, 715–717 (1980). https://doi.org/10.1038/288715a0
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