Copper is a transition metal that is the essential cofactor of the lysyl oxidase (LOX) enzyme — the enzyme that is essential for the cross-linking of collagen and elastin in all connective tissues and that is therefore critical for the structural integrity of blood vessels, bones, tendons, skin, and the other tissues that depend on properly cross-linked collagen and elastin. Copper is also the cofactor of the cytochrome c oxidase enzyme (Complex IV of the mitochondrial electron transport chain), of the dopamine beta-hydroxylase enzyme (which converts dopamine to noradrenaline), of the tyrosinase enzyme (which converts tyrosine to melanin), and of the ceruloplasmin (the copper-carrying protein of the blood), all of which are functionally impaired when copper status is marginal or deficient. Copper deficiency is relatively rare in the general population (because copper is present in a wide range of foods and because the body has efficient mechanisms for copper absorption and retention), but it can develop in people with conditions that impair copper absorption (including celiac disease, Crohn disease, and other conditions that involve the surgical removal or the inflammatory damage of the duodenum and proximal jejunum, where copper is absorbed) and in people who consume high levels of zinc supplementation (which induces the copper-absorbing protein metallothionein in the enterocyte, trapping copper in the enterocyte and preventing its absorption).
Copper and the Lysyl Oxidase Enzyme
The lysyl oxidase (LOX) enzyme is the enzyme that is essential for the formation of the covalent cross-links between adjacent collagen and elastin molecules in all connective tissues. The LOX reaction is an oxidative deamination — it removes the epsilon-amino group from specific lysine and hydroxylysine residues in the collagen and elastin molecules, generating reactive aldehyde groups that spontaneously form covalent cross-links with adjacent lysine or hydroxylysine residues on neighbouring collagen and elastin molecules. These cross-links — the pyridinoline and deoxypyridinoline cross-links that are formed between adjacent collagen molecules — are the primary determinants of the tensile strength and mechanical properties of mature collagen and elastin fibres, and without adequate LOX activity (and therefore without adequate copper), the cross-linking of collagen and elastin is impaired, and the connective tissues that depend on these cross-links are mechanically weakened. The clinical manifestations of copper deficiency include the aortic aneurysm (which results from the weakening of the aortic wall due to impaired elastin cross-linking), the tortuosity and the fragility of the blood vessels (which are the hallmark of the copper-deficient phenotype), the bone fragility (which results from impaired collagen cross-linking in bone), and the skin laxity and the joint hypermobility that are the hallmark of the connective tissue dysfunction in copper deficiency.
The clinical importance of copper for LOX activity is most clearly demonstrated by Menkes disease — the X-linked recessive disorder of copper transport that is caused by mutations in the ATP7A gene, which encodes the copper-transporting ATPase that is essential for the absorption and the distribution of copper in the body. In Menkes disease, the copper that is absorbed from the gut cannot be transported to the peripheral tissues, leading to a severe deficiency of copper in all tissues (including the brain, where the copper is required for the dopamine beta-hydroxylase and for the cytochrome c oxidase) and to a clinical syndrome that includes kinky hair, growth retardation, neurological degeneration, and death in early childhood. The treatment of Menkes disease involves copper supplementation (as copper histidine), which can partially correct the copper transport defect and improve the clinical outcome in some patients.
Copper and Neurodegeneration
Copper also has important functions in the brain, where it is required for the activity of the dopamine beta-hydroxylase (which converts dopamine to noradrenaline), for the activity of the cytochrome c oxidase (which is essential for mitochondrial ATP production in neurons), and for the activity of the superoxide dismutase (SOD1, which is the primary cytosolic antioxidant enzyme in neurons). The copper deficiency that is associated with the neurodegenerative process in Alzheimer disease and in other neurodegenerative conditions is thought to contribute to the mitochondrial dysfunction, the oxidative stress, and the neurotransmitter deficiency that are the hallmarks of these conditions. Copper supplementation in people with copper deficiency (which is uncommon but which can develop in people with conditions that impair copper absorption) improves the neurological outcome and reduces the cognitive impairment that is associated with copper deficiency.
Practical Application
For general copper supplementation (for the prevention and treatment of copper deficiency), the evidence-based dose is 1-2mg of copper daily (as copper gluconate, copper sulfate, or copper citrate, the commonly used forms), taken with a meal for optimal absorption. Copper should not be taken at the same time as zinc or as high-dose iron supplements (which compete with copper for absorption) — it should be taken separately from these minerals, ideally 2 hours apart. The RDA for copper is 900mcg daily for adults, and most people in the developed world achieve this from a varied diet that includes shellfish (oysters are the richest source), nuts, seeds, whole grains, and chocolate. Copper is generally well-tolerated with no significant adverse effects at therapeutic doses, though chronic supplementation above 10mg daily should be avoided because copper is a pro-oxidant metal that can contribute to oxidative stress when present in excess. For comprehensive connective tissue and neurological support, copper pairs well with the vitamin C (which enhances copper absorption and which supports the LOX enzyme that requires copper for its activity), with the zinc (which competes with copper for absorption and which must be balanced against copper intake to prevent zinc-induced copper deficiency), with the manganese (which is required for the activity of the manganese SOD enzyme in mitochondria and which is antagonised by copper), and with the B-complex vitamins (which are required for the function of the dopamine beta-hydroxylase and for the synthesis of the neurotransmitters that are affected in copper deficiency).
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