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Copper peptide GHK-Cu

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Copper peptide GHK-Cu

Tripeptide
Names
IUPAC name
6-Amino-2-[[2-[(2-aminoacetyl)amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoic acid
Other names
Glycyl-L-Histidyl-L-Lysine; Growth-modulating peptide; Kollaren; Liver cell growth factor; Liver growth factor Cu-GHK; Glycyl-histidyl-lysine, monocopper salt, Prezatide copper[1]
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
UNII
  • InChI=1S/C14H24N6O4/c15-4-2-1-3-10(14(23)24)20-13(22)11(19-12(21)6-16)5-9-7-17-8-18-9/h7-8,10-11H,1-6,15-16H2,(H,17,18)(H,19,21)(H,20,22)(H,23,24)
    Key: MVORZMQFXBLMHM-UHFFFAOYSA-N
  • (Cu complex): InChI=1S/C14H24N6O4.Cu/c15-4-2-1-3-10(14(23)24)20-13(22)11(19-12(21)6-16)5-9-7-17-8-18-9;/h7-8,10-11H,1-6,15-16H2,(H,17,18)(H,19,21)(H,20,22)(H,23,24);
    Key: DIWZQABMLHSNJR-UHFFFAOYSA-N
  • O=C(N[C@@H](CC1=CN=CN1)C(N[C@@H](CCCCN)C(O)=O)=O)CN
  • (Cu complex): C1=C(NC=N1)CC(C(=O)NC(CCCCN)C(=O)O)NC(=O)CN.[Cu]
Properties
C14H24N6O4
C14H22CuN6O4 (Cu complex)
Molar mass 340.38 g/mol
130.98 g/L [2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Copper peptide GHK-Cu is a naturally occurring copper complex of the tripeptide glycyl-L-histidyl-L-lysine. The tripeptide has strong affinity for copper(II) and was first isolated from human plasma. It can be found also in saliva and urine.

Overview

[edit]

Several copper(II)-peptide complexes occur naturally.[3] In human plasma, the level of GHK-Cu is about 200 ng/ml at age 20. By the age of 60, the level drops to 80 ng/ml. In humans, GHK-Cu is proposed to promote wound healing, attraction of immune cells, antioxidant and anti-inflammatory effects, stimulation of collagen and glycosaminoglycan synthesis in skin fibroblasts and promotion of blood vessels growth. Recent studies revealed its ability to modulate expression of a large number of human genes, generally reversing gene expression to a healthier state. Synthetic GHK-Cu is used in cosmetics as a reparative and anti-aging ingredient.[4]

History

[edit]

Loren Pickart (1938-2023) isolated the copper peptide GHK-Cu from human plasma albumin in 1973.[5] It was noticed that liver tissue obtained from patients aged 60 to 80 years had an increased level of fibrinogen. However, when liver cells from old patients were incubated in the blood from the younger group, the older cells started functioning in nearly the same way as the younger liver tissue.[6][7] It turned out that this effect was due to a small peptide factor that behaved similarly to the synthetic peptide glycyl-L-histidyl-L-lysine (GHK). Pickart proposed that this activity in human plasma albumin was a tripeptide glycyl-L-histidyl-L-lysine and that it might function by chelating metal ions.[8]

In 1977, the growth modulating peptide was shown to be a glycyl-L-histidyl-L-lysine.[9] It is proposed that GHK-Cu modulates copper intake into cells.[10]

Wound healing

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Biochemical studies

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In the late 1980s, copper peptide GHK-Cu started attracting attention as a promising wound healing agent. At picomolar to nanomolar concentrations, GHK-Cu stimulated the synthesis of collagen in skin fibroblasts, increased accumulation of total proteins, glycosaminoglycans (in a biphasic curve) and DNA in the dermal wounds in rats. They also found out that the GHK sequence is present in collagen and suggested that the GHK peptide is released after tissue injury.[11][12] They proposed a class of emergency response molecules which are released from the extracellular matrix at the site of an injury.[13] GHK-Cu also increased synthesis of decorin – a small proteoglycan involved in the regulation of collagen synthesis, wound healing regulation and anti-tumor defense.[14]

It was also established that GHK-Cu stimulates both the synthesis of metalloproteinases, the enzymes which break down dermal proteins, and their inhibitors (anti-proteases). The fact that GHK-Cu not only stimulates the production of dermal components, but also regulates their breakdown suggests that it should be used with caution.[15]

Wound healing in animals

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A series of animal experiments established pronounced wound healing activity of GHK-Cu. In the dermal wounds of rabbits GHK-Cu facilitated wound healing, causing better wound contraction, faster development of granular tissue and improved angiogenesis. It also elevated the level of antioxidant enzymes.[16][17]

GHK-Cu has been found to induce a systemic enhancement of healing in rats, mice, and pigs; that is, the GHK-Cu peptide injected in one area of the body (such as the thigh muscles) improved healing at distant body areas (such as the ears). These treatments strongly increased healing parameters such as collagen production, angiogenesis, and wound closure in both wound chambers and full thickness wounds.[18] In one study, full‐thickness wounds of 6 millimeters in diameter were created in an ischemic skin flap on the backs of rats, and for 13 days the wound sites were then treated daily with topical GHK or topical hydroxypropyl methylcellulose vehicle, or given no treatment. At the end of the study, the wound size had decreased by 64.5% in the GHK group; by 45.6% in the vehicle-treated group; and by 28.2% in the control group.[19] The difference between the GHK group's wounds and those of the control group was significant, and was accompanied by significantly lower levels of tumor necrosis factor alpha and elastin-degrading matrix metalloproteinases.[19]

Biotinylated GHK-Cu was incorporated into a collagen membrane, which was used as a wound dressing. This GHK-Cu enriched material stimulated wound contraction and cell proliferation, as well as increased expression of antioxidant enzymes. The same material was tested for wound healing in diabetic rats. GHK-Cu treatment resulted in faster wound contraction and epithelization, higher level of glutathione and ascorbic acid, increased synthesis of collagen, and activation of fibroblasts and mast cells.[20] Ischemic open wounds in rats treated with GHK-copper healed faster and had decreased concentration of metalloproteinases 2 and 9 as well as of tumor necrosis factor-beta (a major inflammatory cytokine) compared with vehicle alone or with untreated wounds.[19]

Cosmetic use

[edit]

Copper peptide GHK-Cu is widely used in anti-aging cosmetics (INCI name: Copper tripeptide-1).[21] Several controlled facial studies confirmed anti-aging, firming and anti-wrinkle activity of copper peptide GHK-Cu.[22]

Biological chemistry

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Copper binding

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Replacement of histidine with other amino acids showed that the glycine residue plays major role in copper binding, whereas lysine can interact with copper only at alkaline pH. At physiological pH, lysine is able to interact with a cellular receptor. The ability of GHK to interact both with copper and with a cellular receptor may allows it to transfer copper into and from cells. The small size of GHK permits speedy traveling in extracellular space and its easy access to cellular receptors.[23]

The molecular structure of the GHK copper complex (GHK-Cu) has been determined by X-ray crystallography, EPR spectroscopy, X-ray absorption spectroscopy, NMR spectroscopy, as well as other methods such as titration. In the GHK-Cu complex, the Cu (II) ion is coordinated by the nitrogen from the imidazole side chain of the histidine, another nitrogen from the alpha-amino group of glycine and the deprotonated amide nitrogen of the glycine–histidine peptide bond. Since such a structure could not explain a high stability constant of the GHK-Cu complex (log 10 =16.44 vs. 8.68 of the GH copper complex, which is similar to the GHK-Cu structure), it was proposed that another amino group participates in the complex formation. Cu(II) is also coordinated by the oxygen from the carboxyl group of the lysine from the neighboring complex. Another carboxyl group of lysine from a neighboring complex provides the apical oxygen, resulting in the square-planar pyramid configuration.[24] Many researchers proposed that at the physiological pH, GHK-Cu complexes can form binary and ternary structures which may involve amino acid histidine and/or the copper binding region of the albumin molecule. Lau and Sarkar found also that GHK can easily obtain copper 2+ bound to other molecules such as the high affinity copper transport site on plasma albumin (albumin binding constant log 10 =16.2 vs. GHK binding constant 16 log 10 =16.44). It has been established that copper (II) redox activity is silenced when copper ions are complexed with the GHK tripeptide, which allows the delivery of non-toxic copper into the cell.[25]

Biological significance

[edit]

Copper is vital for all eukaryotic organisms from microbes to humans. A dozen enzymes (cuproenzymes) use changes in copper oxidation state to catalyze important biochemical reactions including cellular respiration (cytochrome c oxidase), antioxidant defense (ceruloplasmin, superoxide dismutase (SOD), detoxification (metallothioneins), blood clotting (blood clotting factors V and VIII), melanin production (tyrosinase) and the connective tissue formation (lysyl peroxidase). Copper is required for iron metabolism, oxygenation, neurotransmission, embryonic development and many other essential biological processes. Another function of copper is signaling – for example, stem cells require a certain level of copper in the media to start their differentiation into cells needed for repair. Thus, GHK-Cu's ability to bind copper and to modulate its tissue level is a key factor determining its biological activity.[26]

See also

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References

[edit]
  1. ^ "Prezatide copper".
  2. ^ "Archived copy" (PDF). Archived from the original (PDF) on 2012-03-24. Retrieved 2011-05-15.{{cite web}}: CS1 maint: archived copy as title (link)
  3. ^ "The Magic of Copper Peptides Science". Archived from the original on 2013-01-19. Retrieved 2012-05-16.
  4. ^ Pickart, L (2008). "The human tri-peptide GHK and tissue remodeling". Journal of Biomaterials Science, Polymer Edition. 19 (8): 969–988. doi:10.1163/156856208784909435. PMID 18644225. S2CID 9354138.
  5. ^ Pickart, L; Thaler, MM (1973). "Tripeptide in human serum which prolongs survival of normal liver cells and stimulates growth in neoplastic liver". Nature New Biology. 243 (124): 85–87. PMID 4349963.
  6. ^ Pilgeram, L; Pickart, L (1968). "Control of fibrinogen biosynthesis; the role of free fatty acids". Journal of Atherosclerosis Research. 8 (1): 155–166. doi:10.1016/s0368-1319(68)80089-4. PMID 5642099.
  7. ^ Pilgeram, L (2010). "Control of fibrinogen biosynthesis; role of FFA/Albumin Ratio". Cardiovascular Engineering. 10 (2): 78–83. doi:10.1007/s10558-010-9092-1. PMC 2885297. PMID 20383582.
  8. ^ Pickart, L (1973), A tripeptide in human plasma that increases the survival of hepatocytes and the growth of hepatoma cells, Ph.D. Thesis in Biochemistry: University of California, San Francisco
  9. ^ Schlesinger, DH; Pickart, L; Thaler, MM (1977). "Growth-modulating serum tripeptide is glycyl-histidyl-lysine". Cellular and Molecular Life Sciences. 33 (3): 324–325. doi:10.1007/BF02002806. PMID 858356. S2CID 29422959.
  10. ^ Pickart, L; Freedman, JH; Loker, WJ; et al. (1980). "Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells". Nature. 288 (5792): 715–717. Bibcode:1980Natur.288..715P. doi:10.1038/288715a0. PMID 7453802. S2CID 4304271.
  11. ^ Maquart, FX; Pickart, L; Laurent, M; Gillery, P; Monboisse, JC; Borel, JP (1988). "Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+". FEBS Letters. 238 (2): 343–6. Bibcode:1988FEBSL.238..343M. doi:10.1016/0014-5793(88)80509-x. PMID 3169264. S2CID 19289897.
  12. ^ Wegrowski, Y.; Maquart, F.X.; Borel, J.P. (1992). "Stimulation of sulfated glycosaminoglycan synthesis by the tripeptide-copper complex Glycyl-L-histidyl-L-lysine-Cu2+". Life Sciences. 51 (13): 1049–1056. doi:10.1016/0024-3205(92)90504-i. PMID 1522753.
  13. ^ Maquart, FX; Bellon, G; Pasco, S; Monboisse, JC (2005). "Matrikines in the regulation of extracellular matrix degradation". Biochimie. 87 (3–4): 353–60. doi:10.1016/j.biochi.2004.10.006. PMID 15781322.
  14. ^ Siméon, A; Wegrowski, Y; Bontemps, Y; Maquart, FX (2000). "Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(2+)". The Journal of Investigative Dermatology. 115 (6): 962–8. doi:10.1046/j.1523-1747.2000.00166.x. PMID 11121126.
  15. ^ Siméon, Alain; Emonard, Hervé; Hornebeck, William; Maquart, François-Xavier (2000). "The tripeptide-copper complex glycyl-L-histidyl-L- lysine-Cu2+ stimulates matrix metalloproteinase-2 expression by fibroblast cultures". Life Sciences. 67 (18): 2257–2265. doi:10.1016/s0024-3205(00)00803-1. PMID 11045606.
  16. ^ Gul, NY; Topal, A; Cangul, IT; Yanik, K (2008). "The effects of topical tripeptide copper complex and helium-neon laser on wound healing in rabbits". Veterinary Dermatology. 19 (1): 7–14. doi:10.1111/j.1365-3164.2007.00647.x. PMID 18177285.
  17. ^ Cangul, IT; Gul, NY; Topal, A; Yilmaz, R (2006). "Evaluation of the effects of topical tripeptide-copper complex and zinc oxide on open-wound healing in rabbits". Veterinary Dermatology. 17 (6): 417–23. doi:10.1111/j.1365-3164.2006.00551.x. PMID 17083573.
  18. ^ Pickart L. Compositions for accelerating wound healing in mammals containing cupric salt or complexes with amino acid or peptide. US Patent 5,164,367, 1992.
  19. ^ a b c Canapp SO Jr, Farese JP, Schultz GS, Gowda S, Ishak AM, Swaim SF, Vangilder J, Lee-Ambrose L, Martin FG (Nov–Dec 2003). "The effect of topical tripeptide-copper complex on healing of ischemic open wounds". Veterinary Surgery. 32 (6): 515–23. doi:10.1111/j.1532-950x.2003.00515.x. PMID 14648529.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Kartha, R; Jayakumar, R (2007). "A therapeutic approach for diabetic wound healing using biotinylated GHK incorporated collagen matrices". Life Sciences. 80 (4): 275–84. doi:10.1016/j.lfs.2006.09.018. PMID 17049946.
  21. ^ Gorouhi, F.; Maibach, H.I. (2009). "Role of topical peptides in preventing and treating aged skin". International Journal of Cosmetic Science. 31 (5): 327–345. doi:10.1111/j.1468-2494.2009.00490.x. PMID 19570099. S2CID 205584531.
  22. ^ Pickart-Margolina (2018). "Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data". International Journal of Molecular Sciences. 19 (7): 7. doi:10.3390/ijms19071987. PMC 6073405. PMID 29986520.
  23. ^ Conato, Chiara; Gavioli, Riccardo; Guerrini, Remo; Kozłowski, Henryk; Młynarz, Piotr; Pasti, Claudia; Pulidori, Fernando; Remelli, Maurizio (2001). "Copper complexes of glycyl-histidyl-lysine and two of its synthetic analogues: Chemical behaviour and biological activity". Biochimica et Biophysica Acta (BBA) - General Subjects. 1526 (2): 199–210. doi:10.1016/s0304-4165(01)00127-1. PMID 11325542.
  24. ^ Hureau, C.; Eury, H.; Guillot, R.; Bijani, C.; Sayen, S.; Solari, P.L.; Guillon, E.; Faller, P.; Dorlet, P (2011). "X-ray and solution structures of Cu(II) GHK and Cu(II) DAHK complexes: influence on their redox properties". Chemistry: A European Journal. 17 (36): 10151–60. doi:10.1002/chem.201100751. PMID 21780203.
  25. ^ Lau, S.J.; Sarkar, B. (1981). "The interaction of copper(II) and glycyl-L-histidyl-L-lysine, a growth-modulating tripeptide from plasma". Biochemical Journal. 199 (3): 649–56. doi:10.1042/bj1990649. PMC 1163421. PMID 7340824.
  26. ^ Pickart L. The human tripeptide GHK (Glycyl-L-histidyl-L-Lysine), the copper switch and the treatment of the degenerative conditions of aging. In Anti-Aging Therapeutics Volume XI, 301-3012. Ed. By Klatz R. and Goldman R. Chicago, IL, USA: American Academy of Medicine, 2009
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