copper in biology copper in biology copper is an essential trace element that is vital to the health of all living things (plants, animals and microorganisms). in humans, copper is essential to the proper functioning of organs and metabolic processes. the human body has complex homeostatic mechanisms which attempt to ensure a constant supply of available copper, while eliminating excess copper whenever this occurs. however, like all essential elements and nutrients, too much or too little nutritional ingestion of copper can result in a corresponding condition of copper excess or deficiency in the body, each of which has its own unique set of adverse health effects. normal absorption and distribution of copper. cu = copper, cp = ceruloplasmin, green = atp7b carrying copper. daily dietary standards for copper have been set by various health agencies around the world. standards adopted by some nations recommend different copper intake levels for adults, pregnant women, infants, and children, corresponding to the varying need for copper during different stages of life. biochemistry copper proteins have diverse roles in biological electron transport and oxygen transportation, processes that exploit the easy interconversion of cu(i) and cu(ii). copper is essential in the aerobic respiration of all eukaryotes. in mitochondria, it is found in cytochrome c oxidase, which is the last protein in oxidative phosphorylation. cytochrome c oxidase is the protein that binds the o2 between a copper and an iron; the protein transfers 4 electrons to the o2 molecule to reduce it to two molecules of water. copper is also found in many superoxide dismutases, proteins that catalyze the decomposition of superoxides by converting it (by disproportionation) to oxygen and hydrogen peroxide: cu+-sod + o2− + 2h+ → cu2+-sod + h2o2 (oxidation of copper; reduction of superoxide) cu2+-sod + o2− → cu+-sod + o2 (reduction of copper; oxidation of superoxide) the protein hemocyanin is the oxygen carrier in most mollusks and some arthropods such as the horseshoe crab (limulus polyphemus). because hemocyanin is blue, these organisms have blue blood rather than the red blood of iron-based hemoglobin. structurally related to hemocyanin are the laccases and tyrosinases. instead of reversibly binding oxygen, these proteins hydroxylate substrates, illustrated by their role in the formation of lacquers. the biological role for copper commenced with the appearance of oxygen in earth's atmosphere. several copper proteins, such as the "blue copper proteins", do not interact directly with substrates; hence they are not enzymes. these proteins relay electrons by the process called electron transfer. photosynthesis functions by an elaborate electron transport chain within the thylakoid membrane. a central link in this chain is plastocyanin, a blue copper protein. a unique tetranuclear copper center has been found in nitrous-oxide reductase. chemical compounds which were developed for treatment of wilson's disease have been investigated for use in cancer therapy. optimal copper levels copper deficiency and toxicity can be either of genetic or non-genetic origin. the study of copper's genetic diseases, which are the focus of intense international research activity, has shed insight into how human bodies use copper, and why it is important as an essential micronutrient. the studies have also resulted in successful treatments for genetic copper excess conditions, empowering patients whose lives were once jeopardized. researchers specializing in the fields of microbiology, toxicology, nutrition, and health risk assessments are working together to define the precise copper levels that are required for essentiality, while avoiding deficient or excess copper intakes. results from these studies are expected to be used to fine-tune governmental dietary recommendation programs which are designed to help protect public health. essentiality copper is an essential trace element (i.e., micronutrient) that is required for plant, animal, and human health. it is also required for the normal functioning of aerobic (oxygen-requiring) microorganisms. copper's essentiality was first discovered in 1928, when it was demonstrated that rats fed a copper-deficient milk diet were unable to produce sufficient red blood cells. the anemia was corrected by the addition of copper-containing ash from vegetable or animal sources. fetuses, infants, and children human milk is relatively low in copper, and the neonate's liver stores falls rapidly after birth, supplying copper to the fast-growing body during the breast feeding period. these supplies are necessary to carry out such metabolic functions as cellular respiration, melanin pigment and connective tissue synthesis, iron metabolism, free radical defense, gene expression, and the normal functioning of the heart and immune systems in infants. since copper availability in the body is hindered by an excess of iron and zinc intake, pregnant women prescribed iron supplements to treat anemia or zinc supplements to treat colds should consult physicians to be sure that the prenatal supplements they may be taking also have nutritionally-significant amounts of copper. when newborn babies are breastfed, the babies' livers and the mothers' breast milk provide sufficient quantities of copper for the first 4–6 months of life. when babies are weaned, a balanced diet should provide adequate sources of copper. cow's milk and some older infant formulas are depleted in copper. most formulas are now fortified with copper to prevent depletion. most well-nourished children have adequate intakes of copper. health-compromised children, including those who are premature, malnourished, have low birth weights, develop infections, and who experience rapid catch-up growth spurts, are at elevated risk for copper deficiencies. fortunately, diagnosis of copper deficiency in children is clear and reliable once the condition is suspected. supplements under a physician's supervision usually facilitate a full recovery. homeostasis copper is absorbed, transported, distributed, stored, and excreted in the body according to complex homeostatic processes which ensure a constant and sufficient supply of the micronutrient while simultaneously avoiding excess levels. if an insufficient amount of copper is ingested for a short period of time, copper stores in the liver will be depleted. should this depletion continue, a copper health deficiency condition may develop. if too much copper is ingested, an excess condition can result. both of these conditions, deficiency and excess, can lead to tissue injury and disease. however, due to homeostatic regulation, the human body is capable of balancing a wide range of copper intakes for the needs of healthy individuals. many aspects of copper homeostasis are known at the molecular level. copper's essentiality is due to its ability to act as an electron donor or acceptor as its oxidation state fluxes between cu1+(cuprous) and cu2+ (cupric). as a component of about a dozen cuproenzymes, copper is involved in key redox (i.e., oxidation-reduction) reactions in essential metabolic processes such as mitochondrial respiration, synthesis of melanin, and cross-linking of collagen. copper is an integral part of the antioxidant enzyme copper-zinc superoxide dismutase, and has a role in iron homeostasis as a cofactor in ceruloplasmin. a list of some key copper-containing enzymes and their functions is summarized below: key copper-containing enzymes and their functions enzymesfunction amine oxidasesgroup of enzymes oxidizing primary amines (e.g., tyramine, histidine and polylamines) ceruloplasmin (ferroxidase i)multi-copper oxidase in plasma, essential for iron transport cytochrome c oxidaseterminal oxidase enzyme in mitochondrial respiratory chain, involved in electron transport dopamine beta-hydroxylaseinvolved in catecholamine metabolism, catalyzes conversion of dopamine to norepinephrine hephaestinmulti-copper ferroxidase, involved in iron transport across intestinal mucosa into portal circulation lysyl oxidasecross-linking of collagen and elastin peptidylglycine alpha-amidating mono-oxygenase (pam)multifunction enzyme involved in maturation and modification of key neuropeptides (e.g., neurotransmitters, neuroendocrine peptides) superoxide dismutase (cu, zn)intracellular and extracellular enzyme involved in defense against reactive oxygen species (e.g., destruction of superoxide radicals) tyrosinaseenzyme catalyzing melanin and other pigment production the transport and metabolism of copper in living organisms is currently the subject of much active research. copper transport at the cellular level involves the movement of extracellular copper across the cell membrane and into the cell by specialized transporters. in the bloodstream, copper is carried throughout the body by albumin, ceruloplasmin, and other proteins. the majority of blood copper (or serum copper) is bound to ceruloplasmin. the proportion of ceruloplasmin-bound copper can range from 70 to 95% and differs between individuals, depending, for example, on hormonal cycle, season, and copper status. intracellular copper is routed to sites of synthesis of copper-requiring enzymes and to organelles by specialized proteins called metallochaperones. another set of these transporters carries copper into subcellular compartments. certain mechanisms exist to release copper from the cell. specialized transporters return excess unstored copper to the liver for additional storage and/or biliary excretion. these mechanisms ensure that free unbound toxic ionic copper is unlikely to exist in the majority of the population (i.e., those without genetic copper metabolism defects). absorption in mammals copper is absorbed in the stomach and small intestine, although there appear to be differences among species with respect to the site of maximal absorption. copper is absorbed from the stomach and duodenum in rats and from the lower small intestine in hamsters. the site of maximal copper absorption is not known for humans, but is assumed to be the stomach and upper intestine because of the rapid appearance of 64cu in the plasma after oral administration. absorption of copper ranges from 15 to 97%, depending on copper content, form of the copper, and composition of the diet. various factors influence copper absorption. for example, copper absorption is enhanced by ingestion of animal protein, citrate, and phosphate. copper salts, including copper gluconate, copper acetate, or copper sulfate, are more easily absorbed than copper oxides. elevated levels of dietary zinc, as well as cadmium, high intakes of phytate and simple sugars (fructose, sucrose) inhibit dietary absorption of copper. furthermore, low levels of dietary copper inhibit iron absorption. some forms of copper are not soluble in stomach acids and cannot be absorbed from the stomach or small intestine. also, some foods may contain indigestible fiber that binds with copper. high intakes of zinc can significantly decrease copper absorption. extreme intakes of vitamin c or iron can also affect copper absorption, reminding us of the fact that micronutrients need to be consumed as a balanced mixture. this is one reason why extreme intakes of any one single micronutrient are not advised. individuals with chronic digestive problems may be unable to absorb sufficient amounts of copper, even though the foods they eat are copper-rich. several copper transporters have been identified that can move copper across cell membranes. other intestinal copper transporters may exist. intestinal copper uptake may be catalyzed by ctr1. ctr1 is expressed in all cell types so far investigated, including enterocytes, and it catalyzes the transport of cu+1 across the cell membrane. excess copper (as well as other heavy metal ions like zinc or cadmium) may be bound by metallothionein and sequestered within intracellular vesicles of enterocytes (i.e., predominant cells in the small intestinal mucosa). distribution copper released from intestinal cells moves to the serosal (i.e., thin membrane lining) capillaries where it binds to albumin, glutathione, and amino acids in the portal blood. there is also evidence for a small protein, transcuprein, with a specific role in plasma copper transport several or all of these copper-binding molecules may participate in serum copper transport. copper from portal circulation is primarily taken up by the liver. once in the liver, copper is either incorporated into copper-requiring proteins, which are subsequently secreted into the blood. most of the copper (70 – 95%) excreted by the liver is incorporated into ceruloplasmin, the main copper carrier in blood. copper is transported to extra-hepatic tissues by ceruloplasmin, albumin and amino acids, or excreted into the bile. by regulating copper release, the liver exerts homeostatic control over extra-hepatic copper. excretion bile is the major pathway for the excretion of copper and is vitally important in the control of liver copper levels. most fecal copper results from biliary excretion; the remainder is derived from unabsorbed copper and copper from desquamated mucosal cells. postulated spectrum of copper metabolism dose rangeapproximate daily intakeshealth outcomes death gross dysfunction and disturbance of metabolism of other nutrients; hepatic "detoxification" and homeostasis overwhelmed toxic>5.0 mg/kg body weightgastrointestinal metallothionein induced (possible differing effects of acute and chronic exposure) 100 μg/kg body weightplateau of absorption maintained; homeostatic mechanisms regulate absorption of copper adequate34 μg/kg body weighthepatic uptake, sequestration and excretion effect homeostasis; glutathione-dependent uptake of copper; binding to metallothionein; and lysosomal excretion of copper 11 μg/kg body weightbiliary excretion and gastrointestinal uptake normal 9 μg/kg body weighthepatic deposit(s) reduced; conservation of endogenous copper; gastrointestinal absorption increased deficient8.5 μg/kg body weightnegative copper balance 5.2 μg/kg body weightfunctional defects, such as