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Copper

Cu

Copper, Cu - Essential Metal

Cu

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: