Protective Functions of β-Alanyl-L-Histidine and Glycyl-L-Histidyl-L-Lysine Glycoconjugates and Copper in Concert.
This review/research paper examines two naturally occurring peptides — carnosine (β-alanyl-L-histidine) and GHK (glycyl-L-histidyl-L-lysine) — and explores strategies to improve their stability and bioavailability through glycoconjugation. A key challenge addressed is the rapid degradation of carnosine by the enzyme carnosinase and the inherent low stability of GHK. The authors report that conjugating these peptides to either trehalose (a disaccharide) or hyaluronan (a polysaccharide) inhibits carnosinase activity and increases tripeptide stability, while also protecting the saccharide components from degradation. The study further investigates copper-binding properties of these glycoconjugates, finding that the saccharide components potentiate the Cu,Zn-superoxide dismutase-like (antioxidant) activity of the resulting copper(II) complexes. The glycoconjugates are reported to act as copper ionophores in cell culture, increasing intracellular copper levels and stimulating copper-driven signaling pathways, leading to enhanced expression of trophic and angiogenic proteins including BDNF, BMP-2, and VEGF. Copper chaperones CCS and Atox-1 are implicated as transcription factors in these pathways. Limitations include reliance on in vitro cell culture models and biochemical assays, with no human clinical data presented.
Why this grade: All reported mechanistic and functional findings are derived from in vitro biochemical assays and cell culture experiments, with no animal models or human subjects included.
Two endogenous peptides, β-alanyl-L-histidine, named carnosine (Car), and glycyl-L-histidyl-L-lysine (GHK), derived from the matricellular protein Secreted Protein Acidic and Rich in Cysteine (SPARC), share many beneficial functions. The hydrolytic enzyme carnosinase for Car and the low stability for GHK can put into question their antioxidant, antiaggregating, and anti-inflammatory properties. The glycoconjugates of Car with a di- (trehalose, Tre) or polysaccharide (hyaluronan, HA) inhibit carnosinase, while the synthesis of HAGHK derivatives increases the tripeptide stability and protects/delays the biopolymer degradation. A synergic effect between the two components of the glycoconjugates is evident in their consequently preserved protective features. TreCar, HACar, and HAGHK maintain the copper-binding ability of the peptides alone, and the saccharides potentiate the Cu,Zn-superoxide dismutase-like ability of the copper(II) complexes with the glycoconjugates. These peptide derivatives behave as copper ionophores, utilizing Cu 2+ present in the culture medium; also, an increase in the metal intracellular level occurs with a consequent stimulation of the copper-driven signaling pathways that produce the expression/release of trophic (Brain-Derived Neurotrophic Factor, BDNF, and Bone Morphogenetic Protein 2, BMP-2) and angiogenic (Vascular Endothelial Growth Factor, VEGF) proteins. Copper chaperons for SOD1, CCS, and Antioxidant 1 (Atox-1) are the copper chaperones that act as transcription factors.
Educational summary of published research — not medical advice. License: cc by. Full text is shown only where licensing permits.