Copper is an essential metal that plays a fundamental role in human biochemistry. The average daily diet contains 0,9 mg of copper, which is absorbed from the stomach and duodenum and appears in the portal circulation bound to albumin and transcuprein. Then it is rapidly extracted by the liver in first-pass kinetics. A little part is not transferred into hepatocyte, but it’s excreted by urine.
Copper is trasported into the cells by the integral membrane protein Ctr1, which is an homotrimer. It is composed by nine transmembrane domains forming a pore in the lipid bilayer, and by several methionine residues that bind copper. Within the cells it is incorpored into metallothionein, which contains many cysteine residues with sulfhydryl groups that allow it to bind heavy metals: at high concentrations, copper can stimulate metallothionein synthesis.
When it is in the cells, copper is bound by chaperones:
- CCS, which transports it to Cu/Zn-binding superoxide dismutase 1(SOD1);
- COX17, involved in the copper transfer to the mitochondrial cytochrome c oxidase
- ATOX1, which transfers it to copper trasporting ATP-ase (ATP7B in hepatocyte and ATP7A in other cells),an enzyme found in Golgi apparatus. Within the hepatocyte, ATP7B provides the metal to essential cuproenzymes and mediates the excretion of excess intracellular copper into plasma (incorpored in ceruloplasmina) and into bile. Mutations in ATP7A or ATP7B disrupt its homeostatic balance, resulting in copper deficiency ( Menkes disease ) or copper overload (Wilson’s disease).
Some enzymes require copper as cofactor:
- cytochrome c oxidase, the last enzyme in the respiratory electron transport chain
- Cu/Zn-binding superoxide dismutase: degrades superoxide to yield peroxide and oxygen, i this way it protects against free-radical damage to proteins, membrane lipids, and nucleic acids.
- ceruloplasmin: exhibits a copper-dependent oxidase activity, which is associated with possible oxidation of Fe2+ (ferrous iron) into Fe3+ (ferric iron)
- mono amino oxidase, involved in catabolism of catecholamines and serothonin
- diamino oxidase
- lysil oxidase: plays a critical role in the biogenesis of connective tissue matrices by crosslinking the extracellular matrix proteins, collagen and elastin
- dopamina beta-hydroxylase W
- tyrosinase: catalyzes the production of melanina and other pigments from tyrosine by oxidation
- coagulation factor V and VIII
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- Ceruloplasmin (Cp)
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