Copper
Cu
Copper, Cu - Essential Metal
Daily Requirement:
Modified DV:
RDA ?:
Adequate Intake ?:
900
true
mcg/day
mcg/day
Min Deficiency:
Max Toxicity:
Tolerable UL
Animal:Plant Conv:
10000
mcg/day
mcg/day
mcg/day
Date Discovered:
1928
Short Description:
Copper is a transition metal able to cycle between two redox states,
oxidized Cu(II) and reduced Cu(I)
•Most organisms require copper as a catalytic cofactor for biological
processes such as respiration, iron transport, oxidative stress protection,
pigmentation, and collagen formation
•Copper plays a vital role as a catalytic co-factor for a variety of
metalloenzymes including:
•superoxide dismutase (for protection against free radicals),
•cytochrome c oxidase (mitochondrial electron transport chain),
•tyrosinase (pigmentation)
•lysyl oxidase (collagen maturation)
•Hephaestin (iron efflux out of cells)
•Dietary intakes of copper for adults range from 0.6 to 1.6 mg copper/day, most of which comes from eating foods rich in copper such as seafood, organ meats, nuts, and seeds
Interpretation:
Copper
• Know some of the Cu dependent enzymes
list of enzymes - which isn't dependent on copper
• Is Cu deficiency a problem
no
• How is copper taken into the enterocytes
CPR1 - transports.
• What is metallothionein, how is it involved in Cu metabolism, how is its expression turned on
Like ferritin, binds transition metals like copper and zinc and cadmium, high copper -> MTF1 goes into nucleus, binds to metalothionein -> turn on expression.
• What mutations cause Wilson’s disease, Menke’s disease, how do these mutations influence Cu homestasis
Wilsons: Toxic accumulation in liver - ATP7b removes excess copper in the liver to the bile. B=bile
Menke: ATP7a - copper into enterocytes, but not into bloodstream. both mutations.
History & Discovery:
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.
Digestion:
Copper Uptake into Intestinal Enterocytes
A metalloreductase reduces Cu2+ to Cu1+ for import by Ctr1
Cu1+ is pumped into the secretory compartment for loading onto Cu-dependent enzymes, or out
In the bloodstream Cu is transported via the portal vein to the liver, a central organ of Cu
In the secretory compartment Cu is loaded onto hephaestin, a multi-Cu ferroxidase that functions
Organismal Copper Metabolism
Absorption and Storage:
•Once absorbed, copper is rapidly distributed to copper-requiring enzymes and only a small fraction is stored in the body
•Regulation of total body copper occurs largely at the small intestine, the major site of copper absorption
•Like iron, the amount of dietary copper absorbed varies considerably with intake:
when intake is less than 1 mg/day, more than 50% of the copper is absorbed; intake more than 5 mg/day, less than 20% is absorbed
•Total body copper levels are also controlled at the liver, which is the principal storage site for copper and regulates its excretion into the bile
•Dietary intakes of copper for adults range from 0.6 to 1.6 mg copper/day, most of which comes from eating foods rich in copper such as seafood, organ meats, nuts, and seeds
Important Pathways:
•Copper is a transition metal able to cycle between two redox states, oxidized Cu(II) and reduced Cu(I)
•Most organisms require copper as a catalytic cofactor for biological processes such as respiration, iron transport, oxidative stress protection, pigmentation, and collagen formation
•Copper plays a vital role as a catalytic co-factor for a variety of metalloenzymes including:
superoxide dismutase (for protection against free radicals),
cytochrome c oxidase (mitochondrial electron transport chain),
tyrosinase (pigmentation)
lysyl oxidase (collagen maturation)
Hephaestin (iron efflux out of cells)
•Like Fe, copper is toxic to cells due to its ability to catalyze Fenton chemistry, which leads to production of the hydroxyl radical, causing catastrophic damage to lipids, proteins and DNA
•Therefore, elaborate mechanisms control cellular uptake, distribution, detoxification and elimination of copper
Copper homeostasis is maintained by:
copper transporters that mediate cellular copper uptake or efflux
copper chaperones, a group of proteins required for binding to imported
Defects in any of these mechanisms can have dire consequences:
Menke’s disease
Wilson’s disease
•These diseases are characterized by the inability to appropriately distribute copper to all cells and tissues
Deficiency Diseases, Detection, Cures:
Acquired copper deficiency in adults
•Typically very rare
•Acquired copper deficiency in adults may occur following increased zinc intake, longterm parenteral nutrition or malabsorption from a variety of causes
•Many of the symptoms associated with copper deficiency are a consequence of
decreased activity of copper-dependent enzymes
•The most commonly reported manifestations of copper deficiency are hematological
and may include neutropenia, thrombocytopenia and anemia.
•Copper deficiency may also result in neurological manifestations. Affected individuals
present with sensory ataxia, hyperreflexia and a spastic gait
•If detected early, copper supplementation always resolves the hematological
manifestations and may prevent further neurological deterioration
Copper Detoxification
Exposure to toxic concentrations of copper will produce an intracellular stress response.
The copper-induced stress response involves altered transcription of multiple genes, which are responsible for maintaining metal homeostasis and protecting cellular components from damage.
To help maintain copper homeostasis and scavenge toxic by-products of copper exposure, cells express metallothioneins (MTs)
MTs are small proteins with a high cysteine content and the ability to bind up to nine copper ions or other metal ions, such as zinc and cadmium
Proposed functions of MTs include maintaining homeostasis for essential metals such as zinc and copper, cellular detoxification, and scavenging free radicals
Elevated concentrations of many transition metals (including copper) have been shown to elicit rapid induction of MT mRNAs and proteins
In addition, a variety of nonmetal stressors such as heat shock, alkylating agents, oxidative stress, and UV radiation induce MT transcription
Metal-inducible MT transcription is regulated primarily through the interaction between metal response elements (MREs) and metal transcription factor (MTF)-1
MREs are 13- to 15-bp upstream regulatory elements with the core consensus sequence CTNTGCRCNCGG that are found in the promoter region of MT genes
MTF-1 specifically binds to the MRE and has been shown to be essential for the metal-inducible transcription of MT
Regulation of MTF-1 binding to the MRE is not well understood
In conditions of Cu excess, MTF-1 is preferentially translocated from the cytoplasm to the nucleus
Additional cis regulatory elements that also regulate inducible MT transcription is the antioxidant response elements (ARE)
The ARE regulate oxidative stress-inducible transcription of many genes, including glutathione genes and MT
Glutathione can also bind excess Cu, glutathione depletion increases Cu toxicity
The ARE-mediated induction of detoxification genes is thought to be a critical mechanism involved in protecting cells from challenges by electrophiles and reactive oxygen species
Low Copper versus High Copper
Schematic view of copper homeostasis in Drosophila
At low copper conditions (top), MTF-1 does not activate metallothionein gene transcription and analogous to mammalian MTF-1, preferentially localizes to the cytoplasm
At conditions of copper excess (bottom), more MTF-1 is recruited to the nucleus and metallothionein genes are strongly transcribed
The copper efflux transporter ATP7, by changing its subcellular localization, removes excess copper from the cell
Genetic Diseases:
Genetic Diseases of Copper Metabolism
Menke's Disease (MD)
Menke’s Disease (MD) is an X-linked recessive disorder characterised by a general copper deficiency
The incidence of the disease is estimated to range between 1:40,000 and 1:350,000
Clinical features of MD are a direct consequence of dysfunction of several copper dependent enzymes because of an inability to load these enzymes with copper
The clinical features of classic MD typically comprise neurological defects (severe mental retardation, neurodegeneration, seizures), growth retardation, hypothermia, laxity of skin and joints, hypopigmentation, and peculiar "kinky" or "steely" hair
Patients present at 2–3 months of age, and owing to the severity of the disorder, death occurs by 3 years of age.
Treatment of MD consists of copper replacement therapy in which the following fundamental issues should be taken into consideration: (1) the block in intestinal absorption of copper must be bypassed, (2) treatment started as early in life as possible, (3) circulating copper must be delivered to the brain, and (4) copper must be available within cells for cuproenzyme biosynthesis
The only currently available treatment option consists of administration of copper–histidine, a naturally occurring copper–amino acid complex in serum
Although copper replacement therapy with copper histidine results in significant improvement in some patients, leading to an increased lifespan, it has not been uniformly beneficial and the prognosis of patients with classic MD remains inevitably poor
The age at which treatment is started and the severity of the disease seem to be among the main determinants for the outcome of this treatment
MD is caused by mutations in the ATP7A gene, which encodes a highly conserved copper translocating ATPase
ATP7A mRNA is expressed in highly in the intestine and notably low in the liver
Wilson's Disease (WD)
Wilson’s Disease (WD) is an autosomal recessive disorder characterized by defective copper excretion, with an estimated incidence between 1:30,000 and 1:100,000
Clinical features of WD result from toxic accumulation of copper, primarily in the liver and the brain, and therefore may include hepatic abnormalities (cirrhosis and chronic hepatitis, culminating in progressive liver failure), neurological defects (parkinsonian features, seizures), and psychiatric symptoms (personality changes, depression, psychosis)
A characteristic feature often found in patients with WD is a deposition of copper in the eye visible as a gold-brown ring around the periphery of the cornea
Treatment of WD focuses on two aspects:
The first aspect is best accomplished by copper chelation therapy
Dietary copper absorption is also efficiently inhibited by zinc ingestion and by omitting copper-rich dietary components. if treatment is ineffective, or in circumstances of fulminant liver failure, liver transplantation provides an effective cure.
The gene mutated in WD, ATP7B, encodes a copper-transporting P-type ATPase that is highly homologous to ATP7A
The expression pattern of ATP7B is strikingly different to that of ATP7A, as ATP7B is most abundantly expressed in the liver
Other tissues that express ATP7B include kidney, brain, lung, heart, mammary gland and placenta
ATP7A and ATP7B
Schematic representation of copper-induced relocalization of ATP7A and ATP7B. Left side depicts an enterocyte, and right side represents a hepatocyte
In both cells, copper enters through the copper transporter 1 (CTR1), and is then distributed via the copper chaperone ATOX1 to ATP7A or ATP7B residing in the trans-golgi network (TGN)
After a rise in copper concentrations, ATP7A and ATP7B relocalize from the TGN to the cell periphery, and in the case of ATP7A also the plasma membrane, to facilitate excretion of copper
The main difference in these two copper transport pathways lies in the direction
In the enterocyte, ATP7A facilitates excretion of copper into the bloodstream at the basolateral side, whereas in the hepatocyte copper is excreted at the apical side into the bile
The numbers indicate localization defects of ATP7A and ATP7B due to MD-causing and WD-causing mutations, respectively: (1) lack of copper responsiveness, resulting in constitutive localization at the TGN, (2) constitutive localization at the cell periphery, and (3) mislocalization at the ER, presumably due to misfolding