Copper1



Copper1


James F. Collins





HISTORICAL HIGHLIGHTS

It was well established almost 200 years ago that copper was a normal constituent of plants and lower marine invertebrates, but not until 1921 was the presence of copper in animal tissues firmly established, when Bodansky conclusively demonstrated that the human brain contains copper (1). Also in this time, a specific physiologic role for copper was identified when investigators found that copper detected in a liver extract was necessary, along with iron salts, to cure experimental anemia in rats (2) and in other mammalian species. Direct evidence of the involvement of copper in human disease was definitively established in the early 1900s, with the first description of Wilson disease (WD) (3), although the fact that this disease was an inborn error of metabolism was not appreciated until several decades later (4). A relationship between low body copper levels and anemia in humans was suspected in the 1930s, but conclusive experimental proof came later. Copper deficiency in humans was first observed in patients with Menkes disease (MD) in 1962 (5), although the underlying physiologic defect was not discovered until a decade later (6). Investigators have now firmly established that copper is an essential human nutrient. Copper is present in body fluids and tissues in the range of parts per million (µg/g) to parts per billion (ng/g). Because of perturbations of normal homeostatic processes that are influenced by high or low copper concentrations, mammals have developed exquisite systems for regulating copper absorption, transport, storage, utilization, and excretion.


CHEMISTRY

Copper has an atomic mass of approximately 63.5 daltons, with two stable isotopes, 63Cu and 65Cu. Of seven radioisotopes of copper, the two with the longest half-lives, 67Cu (˜70 hours) and 64Cu (˜13 hours), along with the two stable isotopes, are most commonly used for experimental analyses of copper metabolism. Copper has two predominant oxidation states, Cu2+ (cupric) and Cu+ (cuprous), and it commonly shifts back and forth during enzymatic reactions. Cu+ copper is highly insoluble in aqueous solutions and is thus strongly complexed (7). Most copper in biologic systems is bound to proteins, through specific interactions with amino acid side chains.


BIOCHEMICAL AND PHYSIOLOGIC FUNCTIONS

Copper serves a prominent role in mammalian biology as an enzymatic cofactor for a host of cuproenzymes. These enzymes, most of which are oxidases, collectively are involved in single electron transfer reactions between
a substrate and molecular oxygen using either oxidized (Cu2+) or reduced copper atoms (Cu+). Detailed descriptions of these proteins and their physiochemical properties and functions are published elsewhere (8, 9). Copper also has well-recognized nonenzymatic functions in diverse physiologic processes such as angiogenesis, gas transport, neurohormone homeostasis, and regulation of gene expression. Several copper-dependent enzymes have been identified in mammals; these are listed in Table 12.1 and are discussed briefly later. Copper-binding proteins, although not discussed in detail here, are also listed in Table 12.1.


Catalytic Functions


Amine Oxidases

These related enzymes function in the oxidative deamination of biogenic primary amines and exist as dimers with two equivalent subunits. In the plasma, small amounts of these proteins catabolize the physiologically active amines histidine, tyramine, and polyamines. These enzymes may also play a role in intracellular signaling through production of hydrogen peroxide (10). Included in this family is vascular adhesion protein-1 (VAP-1), which is purported to be involved in leukocyte trafficking (11).








TABLE 12.1 COPPER-CONTAINING AND COPPER-BINDING PROTEINS IN MAMMALS



















































































































COPPER-CONTAINING ENZYMES


FUNCTION


EFFECT OF COPPER DEFICIENCY


Amine oxidases


Deamination of monoamines and diamines


Variable


Lysyl oxidase (LOX)


Processing of elastin and collagen


Cardiovascular system abnormalities; bone and cartilage instability


Ceruloplasmin (CP)


Ferroxidase; Iron release from storage sites


Decreased activity; iron accumulation in liver, brain, and pancreas


Hephaestin (HP)


Ferroxidase; intestinal iron transport


Decreased activity; decreased intestinal iron absorption


Dopamine β-monooxygenase (DBM)


Catecholamine metabolism


Neuropathologies; hypomyelination of nerve fibers


Tyrosinase (TYR)


Pigmentation; melanin biosynthesis


Hypopigmentation; abnormal keratinization of hair


Peptidylglycine α-amidating monooxygenase (PAM)


Activation of biologically active peptides


Altered central nervous system hormone production; cardiovascular system dysfunction


Cytochrome c oxidase (CCO)


Electron transport system; ATP production


Decreased capacity for oxidative phosphorylation; hypomyelination


Superoxide dismutase 1 (SOD1)


Antioxidant defense


Increased susceptibility to oxygen free radicals


Superoxide dismutase (extracellular) (SOD3)


Antioxidant defense


Increased susceptibility to oxygen free radicals


Zyklopen


Placental iron efflux


Unknown


Monoamine oxidases A and B (MAOA, MAOB)


Degradation of amine neurotransmitters


Unknown


COPPER-BINDING PROTEINS


COPPER-RELATED FUNCTION



α2-Macroglobulin


Transport of copper from site of absorption in intestine to liver


Albumin


Transport of copper from site of absorption in intestine to liver


Amyloid precursor protein (APP)


Copper transport to brain; ferroxidase


ATOX1


Copper chaperone for copper-transporting ATPases; copper-dependent transcription factor


ATP7A


Transport of copper into TGN and out of cells; Menkes disease gene


ATP7B


Transport of copper into TGN; copper excretion in bile; Wilson disease gene


Blood clotting factors V and VIII


Blood clotting; copper dependency unknown


COMMD1


Biliary copper excretion by interaction with ATP7B; disease gene in Bedlington terrier copper toxicosis


CCS


Copper chaperone for SOD1 in cytosol


CTR1


Plasma membrane copper transporter; necessary for copper uptake in intestine, liver, heart, and other tissues


CTR2


Plasma membrane uptake and vesicular copper transport


COX11


Mitochondrial chaperone for cytochrome c oxidase


COX17


Copper delivery from cytoplasm to mitochondrial intermembrane space


Metallothionein (MT)


Intracellular copper storage protein (also binds zinc and cadmium)


Prion protein (PRNP)


Unknown; several possible functions proposed


SCO1


Mitochondrial copper chaperone


SCO2


Mitochondrial copper chaperone


XIAP


Ubiquitination of COMMD1 and CCS


ATP, adenosine triphosphate; COMMD1, copper metabolism (Murr1) domain containing 1; COX11, cytochrome c oxidase assembly homolog (yeast); COX17, cytochrome c oxidase assembly homolog (S. cerevisiae); CTR, copper transporter; XIAP, X-linked inhibitor of apoptosis.



Monoamine Oxidase. Two isoforms of the enzyme monoamine oxidase (MAO) have been identified, MAOA and MAOB; each has distinct tissue localization. Involved in the catabolism of catecholamines, these copper-containing enzymes react with serotonin, norepinephrine, tyramine, and dopamine. Abnormal regulation of MAOs in the body has been associated with depression, substance abuse, attention deficit disorder, and irregular sexual maturation (12).

Diamine Oxidases. This group of related enzymes is found in cells throughout the body. One of these enzymes is involved in the catabolism of histamine. In the stomach, acid production is inhibited, and throughout the body, allergic reactions are attenuated by the inactivation of histamine through a diamine oxidase. These enzymes also inactivate polyamines and thus limit excessive cell growth, a property that potentially has relevance to apoptosis and cancer (13).

Lysyl Oxidase. Lysyl oxidase (LOX), another copper-dependent amine oxidase, initiates cross-linking and thus stabilization of elastin and collagen fibers. LOX is involved in the formation of connective tissue, including bone, blood vessels, skin, lungs, and teeth. LOX has been implicated in diverse pathologic processes such as fibrosis, tumor progression and metastasis, and neurodegenerative and cardiovascular diseases; LOX is, in fact, considered a potential therapeutic target for these pathologic processes (14). Moreover, a family of at least four LOX genes has now been identified (termed LOXlike proteins; LOXL), with all encoded proteins having similar catalytic domains and predicted copper and cofactor-binding sites (15).

Peptidylglycine α-Amidating Monooxygenase. Peptidylglycine α-amidating monooxygenase (PAM) is a highly conserved copper- and ascorbate-dependent enzyme that is essential for the activation of many bioactive peptides, including vasopressin, vasoactive intestinal peptide, α-melanocyte stimulating hormone, cholecystokinin, gastrin, neuropeptide Y, and substance P (16). The nonredundant role of PAM in mammalian physiology has been demonstrated by the finding that the lack of this enzyme in mice leads to embryonic lethality (17).


Ferroxidases

Ceruloplasmin. Ceruloplasmin (CP) is an abundant, circulating, glycoprotein made and secreted by liver that functions in iron release from some tissues by oxidizing ferrous iron for subsequent binding to transferrin for distribution in the blood. A cell membrane-associated (glycophosphatidylinositol [GPI]-linked) CP isoform, which is expressed in hepatocytes, brain, and macrophages, has been discovered. Indications exist that GPI-linked CP may be important for iron efflux from macrophages and possibly other cell types through interaction with the only identified iron export protein, ferroportin1 (Fpn1) (18).

Hephaestin. Hephaestin (HEPH) is a CP-related protein (50% homology) that was originally described as a membrane-anchored, intestinal ferroxidase. HEPH was discovered as the mutant gene causing perturbations in iron homeostasis in the sex-linked anemia (sla) mouse (19). More recent evidence, however, suggested that it is expressed in additional tissues, including the antrum of the stomach, the enteric nervous system, and pancreatic β cells (20). HEPH expression is thought to respond to body copper levels in a manner that modulates its activity and, concomitantly, the absorption of dietary iron (21).


Cytochrome C Oxidase

Cytochrome c oxidase (CCO) is a large complex that consists of 13 protein subunits, 2 heme groups, zinc, magnesium, and 3 copper ions. CCO, which is found in the mitochondria of cells, is the terminal member of the electron transport chain. It reduces molecular oxygen to form water and ultimately allows adenosine triphosphate (ATP) to be produced by the generation of a proton gradient. Activity of CCO depends on adequate copper intake, and mutations affecting assembly or activity are likely lethal.


Dopamine β-Monooxygenase

Dopamine β-monooxygenase (DBM) catalyzes the conversion of dopamine to norepinephrine; it requires copper in each of its four subunits and ascorbate as a cosubstrate. Expression is highest in adrenal medulla, in sympathetic neurons in the peripheral nervous system, and in noradrenergic and adrenergic neurons in the brain (16). In mice, DBM gene inactivation leads to embryonic lethality, thus exemplifying its key role in nervous system physiology (22).


Superoxide Dismutase

Superoxide dismutase (SOD1 and SOD3 [extracellular]) proteins function to scavenge superoxide free radicals to protect against oxidative damage. Two of these proteins require copper (and zinc) for function, copper/zinc-SOD (SOD1) and extracellular SOD (SOD3). SOD1 is a homodimer of approximately 16 kDa found in the cytoplasm of cells, whereas SOD3 is a tetramer of approximately 135 kDa. SOD3, found in lymph, synovial fluid, and plasma, is the predominant extracellular dismutase (23). Evidence supports a role for SOD3 in the development of chronic obstructive pulmonary disease in humans (24).


Tyrosinase

Tyrosinase (TYR) is an enzyme involved in melanin biosynthesis and is required for normal pigmentation. Loss of activity leads to albinism. TYR catalyzes the conversion of tyrosine to dopamine and the subsequent oxidation of dopamine to dopaquinone, steps along the pathway of melanin synthesis. The copper dependency of this process is best exemplified by the achromotrichia observed in copper-deprived domestic and laboratory animals (16).



Physiologic Functions

The necessary presence of copper in several enzymes discussed previously gives us clues to the phenotype of copper deficiency. In many cases, symptoms of copper inadequacy can be linked with decreased activity of one or more of these copper-dependent enzymes.


Connective Tissue Formation

The copper-dependent enzyme LOX is required for normal formation of connective and bone tissue, as well as for the integrity of connective tissue in the heart and vasculature. Copper deficiency thus results in connective tissue disorders, osteoporosis, and bone defects. Skeletal perturbations have been documented in copper-deficient neonates that mirror the bone abnormalities of scurvy (vitamin C deficiency) (25). Moreover, data demonstrated that long-term copper supplementation may decrease bone loss in adult humans (26), but contradictory results have also been obtained (27).


Iron Metabolism

Copper homeostasis is intimately entwined with that of iron (28). The most obvious link is the multicopper ferroxidases, CP and HEPH; the expression and activity of both proteins is effected by dietary copper (and perhaps iron) status. During copper deficiency, CP activity is extremely low, reflecting its need for copper for proper function (29). The net effect of low copper then is that iron efflux from some tissues is impaired, including liver, to the extent of possible pathologic consequence in humans (30). Moreover, copper deficiency results in microcytic, hypochromic anemia resembling that seen in iron deficiency. This finding may be explained by decreased circulating iron levels or an inability of erythroid precursor cells to use iron for hemoglobin synthesis.


Central Nervous System

Copper plays well-known roles in the physiology of the central nervous system (CNS), including brain development. Copper is deposited in the brain late in gestational development and during the perinatal period, and as such, copper deprivation of pregnant or lactating females results in pathologic phenotypes in offspring. Many of the effects of copper deprivation can be ascribed to altered expression or activity of cuproenzymes found in the tissues of the CNS and their susceptibility to body copper levels (16). The essentiality of copper in brain development is perhaps best exemplified by the neuropathologic phenotype of infants with the genetic copper-deficiency disorder MD (31). The tremors, ataxia, perturbations in myelination of nerve fibers (hypomyelination or demyelination), and reductions seen in some neurotransmitters observed during copper deficiency likely result from decreased production of sphingolipids (as mediated by CCO) and decreased activity of dopamine β-hydroxylase and MAO.

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Jul 27, 2016 | Posted by in PUBLIC HEALTH AND EPIDEMIOLOGY | Comments Off on Copper1

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