The nutritional role of copper

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Copper was identified as an essential trace element, first for animals1 and subsequently for humans2 when anaemia was successfully treated by supplementing the diet with a source of copper. Since then the full significance of its role in biological systems has continued to unfold as it has been identified in a large number of vital metalloproteins, as an allosteric component and as a cofactor for catalytic activity. These proteins perform numerous important roles in the body, relating to the maintenance of immune function, neural function, bone health, arterial compliance, haemostasis, and protection against oxidative and inflammatory damage. However, the accurate assessment of copper status is problematic. Functional copper status is the product of many interacting dietary and lifestyle factors, and an adequate marker of body copper status has yet to be identified. Accurate measurement of dietary copper intake is difficult because while a number of dietary factors are known to limit copper bioavailability, the precise molecular mechanisms of copper absorption and metabolism are not completely understood.

Shown in Table 5.1 is a selection of the copper-containing enzymes and proteins known to be important in human systems. A number of these enzymes exhibit oxidative/reductive activity and use molecular oxygen as a co-substrate. In these redox reactions, the ability of copper to cycle between cupric and cuprous states is crucial to its role as electron transfer intermediate. Cytochrome-c

Table 5.1 Human copper-containing proteins, and their functions

Protein

Function

Cytochrome-c oxidase

Cellular energy production

Ferroxidase I (Caeruloplasmin)

Iron oxidation and transport; free radical

scavenging; amine and phenol oxidation;

acute-phase immune response

Ferroxidase II

Iron oxidation

Hephaestin

Iron metabolism

Copper/zinc superoxide dismutase

Antioxidant defence

Extracellular superoxide dismutase

Antioxidant defence

Monoamine oxidase

Brain chemistry

Dopamine ß-hydroxylase

Brain chemistry

Diamine oxidase

Limitation of cell growth, histamine deactivation

Lysyl oxidase

Connective tissue formation

Peptidylglycine a-amidating

Peptide hormone activation

monooxygenase

Prion protein PrP

Antioxidant defence and/or copper sequestration

and transport

Tyrosinase

Melanin synthesis

Albumin

Metal binding in plasma and interstitial fluids

Chaperone proteins

Intracellular copper delivery to specific target

proteins

Chromatin scaffold proteins

Structural integrity of nuclear material

Clotting factors V and VIII

Thrombogenesis

Metallothionein

Metal sequestration

Transcuprein

Copper binding in plasma

oxidase, embedded in the inner mitochondrial membrane, is the terminal link in the electron transport chain. It catalyses the reduction of oxygen to water. One molecule of cytochrome-c oxidase contains three copper atoms and possesses two active sites. At one site two copper atoms receive, from the electron-carrier cytochrome-c, electrons which are then transferred to the second active site, where the third copper atom functions as a reducing agent.3 Because this is the rate-limiting step in electron transport, cytochrome-c oxidase is considered the single most important enzyme of the mammalian cell.

Ferroxidases I and II are plasma glycoproteins. Ferroxidase I, also known as caeruloplasmin, oxidises Fe (II) to Fe (III) without formation of hydrogen peroxide (H2O2) or oxygen radicals. It is primarily this role which gives rise to caeru-loplasmin's well-known antioxidant function. It also scavenges H2O2, superoxide and hydroxyl radicals, and inhibits lipid peroxidation and DNA degradation stimulated by free iron and copper ions.4 Caeruloplasmin is also an acute-phase protein: in acute response to inflammatory cues caeruloplasmin concentration rises, binding free circulating iron and limiting the amount available to participate in oxidative reactions. One molecule of caeruloplasmin contains six copper ions, of which three provide active sites for electron transfer processes, while the remaining three together form an oxygen-activating site for the enzyme's catalytic action.5 Superoxide dismutase (SOD) is another important and well-studied enzyme. In human systems, it exists in several forms, of which two contain copper: the cytosolic copper/zinc variety sometimes termed SOD1, present in most cells; and the extracellular SOD2, found in the plasma and also in certain cell types in the lung, thyroid and uterus.6 SOD catalyses the dismutation of superoxide radicals to hydrogen peroxide and oxygen.

In several amine oxidases, copper acts as an allosteric component, conferring the structure required for catalytic activity. Monoamine oxidase (MAO) inactivates, by deamination, substrates such as serotonin and catecholamines including adrenalin, noradrenalin and dopamine. Tricyclic antidepressants are MOA inhibitors. Diamine oxidase (DAO) deaminates histamine and polyamines involved in cell proliferation. It is present at low levels in the plasma, but at higher concentrations in the small intestine where histamine stimulates acid secretion, in the kidney where it likely inactivates diamines filtered from the blood, and in the placenta, where it is thought to inactivate foetal amines in maternal blood. Lysyl oxidase deaminates lysine and hydroxylysine, which are present as sidechains of immature collagen and elastin molecules. It thereby enables the formation of crosslinks which lend strength and flexibility to mature connective tissue.

Peptidyl-glycine a-amidating mono-oxygenase (PAM) is found in the plasma and in a number of tissues, including the brain. It produces mature, a-amidated, peptide hormones from their glycine-extended precursors. The enzyme contains two copper atoms per molecule.7 Dopamine b-hydroxylase (DpM) is a mono-oxygenase similar to PAM in structure and activity. Found in the adrenal gland and the brain, it catalyses the synthesis of the catecholamines adrenalin and noradrenalin from dopamine. Tyrosinase, or catechol oxidase, is the only enzyme involved in the synthesis of melanin from tyrosine. Tyrosinase first hydroxylates the amino acid to dopa, then oxidises it to dopaquinone. Subsequent reactions

120 The nutrition handbook for food processors Table 5.2 Dietary Reference Values for copper

Dietary Reference Value Copper (mg/d) Source

US EAR US RDA UK RNI WHO AROI

  1. 7 0.9 1.2
  2. 2 to 2 or 3

Food and Nutrition Board, 2001 Food and Nutrition Board, 2001 Department of Health, 1991 WHO International Programme on

Chemical Safety, 1998

leading to melanins occur spontaneously in vitro. Regulation of pigment formation is also provided by tyrosinase, as it can remove substrates from this pathway by catalysing alternative reactions for them.8 Congenital deficiency of tyrosinase results in albinism.

In the nucleus, copper has a structural role as an essential component of chromatin scaffold proteins, which contribute to nuclear stability.9,10 It does not, however, appear to be required for DNA synthesis in mammalian cells. Although in yeast cells, copper has been identified as a component of gene regulatory mechanisms, if equivalent proteins exist in human cells they remain to be identified.11

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