Copper is an essential transition metal that is the foundation of all iron metabolism and of the function of the cytochrome c oxidase enzyme, which is the terminal enzyme of the mitochondrial electron transport chain. The copper-dependent enzyme ceruloplasmin (CP) is the primary copper-containing protein in the blood and is essential for the oxidation of the ferrous iron (Fe2+) to the ferric iron (Fe3+) that is required for the binding of iron to transferrin and for the transport of iron in the plasma. Without adequate copper and ceruloplasmin, the iron cannot be properly oxidised, it accumulates in the tissues (particularly in the liver, the pancreas, and the brain) in the ferrous form, and it produces the tissue damage, the fibrosis, and the neurological dysfunction that are the clinical manifestations of the copper deficiency. This copper-dependent vulnerability of iron metabolism is one of the most important and least appreciated aspects of mineral nutrition, and it explains why the copper deficiency produces the anaemia that is refractory to iron supplementation and why the copper supplementation corrects the anaemia that is associated with the copper deficiency.
Ceruloplasmin and the Iron Metabolism
Ceruloplasmin is the copper-containing ferroxidase enzyme that is synthesised in the liver and that circulates in the plasma at concentrations of approximately 200-400mg/L. It is the primary enzyme that oxidises the ferrous iron (Fe2+) to the ferric iron (Fe3+) that is required for the binding of iron to transferrin and for the transport of iron in the plasma to the sites of erythropoiesis (the bone marrow) and of storage (the liver, the spleen). The ferrous iron that is released from the enterocytes of the duodenum (after the reduction of the dietary ferric iron by the brush border ferrireductase) and from the macrophages of the reticuloendothelial system (after the degradation of the haemoglobin from the aged red blood cells) must be oxidised to the ferric form before it can bind to transferrin, and ceruloplasmin is the primary enzyme that catalyses this oxidation reaction. When copper is deficient and ceruloplasmin synthesis is impaired, the ferrous iron accumulates in the tissues, the transferrin saturation falls, and the iron deficiency anaemia develops — despite the presence of adequate iron stores. This copper-dependent anaemia is the hallmark of the copper deficiency and is one of the most important diagnostic clues to the diagnosis of this condition.
The clinical importance of the ceruloplasmin for the iron metabolism is underscored by the observation that the aceruloplasminemia (a genetic disorder in which ceruloplasmin is not produced) produces a clinical syndrome that is identical to the copper deficiency — the iron accumulates in the liver, the pancreas, and the brain (producing the cirrhosis, the diabetes, and the neurological dysfunction), the plasma iron is low, the transferrin saturation is low, and the anaemia is present. The treatment of the aceruloplasminemia with the plasma infusions (which provide the exogenous ceruloplasmin) or with the copper supplementation (which stimulates the synthesis of the non-functional ceruloplasmin in the one patient with a mutation that does not completely abolish the ceruloplasmin synthesis) is one of the most elegant examples of the targeted therapy in all of metabolic medicine.
Copper and the Cytochrome c Oxidase
Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial electron transport chain — it catalyses the oxidation of the cytochrome c (which carries the electrons from the complex III to the complex IV) and the reduction of the oxygen to water, coupling the electron transfer to the pumping of the protons across the inner mitochondrial membrane and to the synthesis of the ATP. COX is a copper-containing enzyme — it has two copper atoms in the CuA centre (which accepts the electrons from the cytochrome c) and one copper and one zinc atom in the CuB centre (which is the site of the oxygen reduction). Without adequate copper, the COX activity is impaired, the electron transport chain cannot function, the ATP synthesis is reduced, and the cellular energy metabolism collapses — producing the fatigue, the muscle weakness, the encephalopathy, and the multi-organ failure that are the clinical manifestations of the severe copper deficiency. The neurons are particularly dependent on the COX activity because they have a high metabolic rate and because they rely almost exclusively on the oxidative phosphorylation for their ATP supply — this is why the copper deficiency produces the severe neurological dysfunction (including the developmental delay, the hypotonia, the peripheral neuropathy, and the optic neuropathy) that is the hallmark of the Menkes disease and of the other copper deficiency syndromes.
Practical Application
For general copper supplementation, the evidence-based approach is to supplement with 1-3mg of copper daily (as copper gluconate, copper citrate, or copper picolinate — the forms that are well absorbed and well tolerated). The RDA of copper is 900mcg daily for adults, and the tolerable upper intake level is 10mg daily for adults (above which the copper can produce the gastrointestinal symptoms and the liver toxicity). The copper should be taken in the separate dose from the zinc supplement (by at least 2 hours) because the high-dose zinc supplementation interferes with the copper absorption by inducing the metallothionein in the enterocytes (which binds both zinc and copper and prevents their absorption). For comprehensive iron metabolism and antioxidant support, copper pairs well with iron (which is the other major transition metal in the iron metabolism pathway and whose deficiency often coexists with the copper deficiency), with ceruloplasmin (which is the copper-containing protein that is essential for the iron oxidation and the iron transport), with the vitamin C (which enhances the iron absorption and which works synergistically with the copper for the support of the immune function), and with the manganese (which is the other transition metal that is required for the superoxide dismutase enzyme and which works synergistically with the copper for the antioxidant defence).
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