Copper Flashcards
What are the chemical forms of copper?
esstenial micromineral
Cu2+ (cupric)
Cu+ (cuprous)
What is the enzymatic function of copper?
Cofactor of metalloenzymes:
- participates at the catalytic site or allosteric site
- involved in oxidation-reduction reactions
How does copper serve as a cofactor in oxidation-reduction reactions?
- Antioxidant function: Cu/Zn superoxide dismutase (SOD)
- Iron transport: Ceruloplasmin and hephaestin
- Electron transport chain
- Pigment (melanin) synthesis: tyrosinase
- Collagen synthesis (in lysyl oxidase)
- Hormone activation
- Neurological roles
What is copper’s role in Cu/Zn superoxide mutase (SOD)?
Copper’s role in reaction and for enzymes with antioxidant function
Dismutation of superoxide:
Cu2+-SOD + O2− → Cu+-SOD + O2
= reduction of copper
= oxidation of superoxide
Cu+-SOD + O2− + 2H+ → Cu2+-SOD + H2O2
= oxidation of copper
= reduction of superoxide
What is copper’s function in iron transport?
Ceruloplasmin/ferroxidase:
- Ceruloplasmin Cu2+ to Cu+ for oxidization of Fe2+ to Fe3+
- Ceruloplasmin formed in the liver/hephaestin located on the basolateral membrane - oxidation of iron, which is required for cellular iron release and binding of iron in the form of Fe3+ to transferrin
Coupled with the oxidation of ferrous iron (Fe2+) to ferric iron (Fe3+) copper-dependent reaction (hephaestin)
Ceruloplasmin
- transport of copper in plasma
- antioxidant - important in the inflammatory process
What is copper’s function in the electron transport chain?
Cytochrome c oxidase = terminal oxidation step in electron transport chain
What is copper’s function in pigment (melanin) synthesis?
Melanin production pathway - cofactor for the enzyme tyrosinase
What is copper’s function in collagen & elastin synthesis (vis lysyl oxidase?
Copper is required for lysyl oxidase - cross-linking of tissue proteins for the assembly into fibrils
What is copper’s function in hormone activation?
Cu required for amidation of peptides hormones -> critical for hormone function
Hormones includes gastrin, cholecystokinin, calcitonin, thyrotropin, vasopressin
What is copper’s function in neurological roles?
Biogenic amine degradation (in amine oxidases)
- including histamine, dopamine, serotonin, norepinephrine
Norepinephrine synthesis (dopamine monooxygenase)
Suboptimal copper status may result in neurological and physiological manifestations
Copper is involved in oxidation reduction reactions and in this process it is often oxidized from Cu+ to Cu2+ . In order to function again, copper is reduced to Cu+ by:
Vitamin C
What are natural food sources of copper?
Legumes; nuts and seeds; organ meats; shellfish
What is the form of copper in foods?
Cu2+ (cupric) bound to amino acids/proteins
How is copper digested in the body?
Release of Cu2+ from food components via HCl and digestive enzymes: lipase, amylases in the stomach (low pH) and small intestine
In small intestine: Reductase - reduces Cu2+ to Cu+ (mainly absorbed as Cu+ (cuprous)
How is it absorbed in the enterocyte?
Carrier mediated through copper transporter (Ctr-1) - synthesis may be inversely related to status
- High affinity
DMT-1
- lesser affinity
Bound to amino acids via amino acid transporter
What is the overall absorption rate?
Absorption efficiency inversely related to dietary intakes and body copper status
What are enhancers of copper bioavailability?
- Amino acids (His, Cys); glutathione (contains Cys)
- Organic acids (e.g., citric acid, acetic acid)
- Higher acidity (i.e., low pH)
What are inhibtors of copper bioavailability?
- Phytic acid
- Other divalent cations (e.g., Zn, possibly Fe)
- Increased pH
Antacid -> increase in pH -> insolubility -> impaired absorption
What are the 3 possible fates of absorbed copper in enterocytes?
I. Function use intracellularly for biochemical functions
II. Storage of copper in metallothionein
III. Transported through the cytosol bound to chaperone proteins or glutathione, and across the basolateral membrane
How is copper transported from the intestine to the liver?
Passes through the basolateral membrane via ATP7A = copper transporting ATPase (active transport)
Newly absorbed copper bound to proteins through the hepatic portal blood
Utaken via multiple carrier proteins such as Ctr-1, Ctr-2, DMT1 and other
How is copper metabolized in liver cells (hepatic)?
Cytosolic chaperones (Atox1, Cox17, CCS) compete for Cu-GHS pool and sort the Cu to specific destinations
Cu+ bound to chaperone proteins and transferred to trans-Golgi network via ATP7B - incorporated into ceruloplasmin (60%-70% of copper) and other copper-metalloenzymes
- Cu-Atox1 transfers copper to the ATP7B located in the membrane of trans-Golgi network and secretory vesicles
Cox17 transports copper for cytochrome oxidase function in mitochondria
CCS = copper chaperone for superoxide dismutase: transports Cu to SOD
In excess copper, ATP7B moves Cu+ to vesicles -> into bile duct for biliary secretion into intestine
Storage, bound to metallothionein
What is the main role of chaperone proteins in the intracellular movement of copper?
Binding of copper by chaperone proteins pro-oxidant effects
What is the key role of ATP7A?
- Transport of copper through basolateral membrane of enterocyte
- Release of copper from most cells (except liver)
- Transport of copper across blood-brain barrier
What is the key role of ATP7A?
- Transport of copper into Golgi for synthesis of copper-containing enzymes & ceruloplasmin
- Export of copper into bile duct for excretion
How is copper transported to extrahepatic tissues in plasma?
Ceruloplasmin secreted from liver contains 60%-70% of circulating copper in blood
Remaining copper circulates loosely bound to albumin to other proteins
How is copper cellular uptaken, transported and metabolized?
Uptake of ceruloplasmin into tissues via receptors
In cells bound to chaperone proteins
Use for: biochemical needs, storage, or transport out
Release of copper from cells via ATP7A (expressed in most body cells, except liver)
Where does copper homeostasis occur?
Liver = main site for Cu storage and controlling copper homeostasis
How is copper stored?
- Copper influences hepatic, renal and brain metallothionein synthesis, but not intestinal metallothionein synthesis (which is zinc-induced)
- Compared to other trace elements, little is stored
How is copper excreted?
Minor losses: urine, sweat, skin, hairs, nails
* Biliary excretion as a homeostatic mechanism
* Copper bound to bile components, cannot be reabsorbed
* Copper excretion into bile involves ATP7B
What are the health implications of deficiency?
Rare in adults = more likely with high Zn intake or meds that reduce Cu absorption
What are copper deficiency symptoms?
Reduced activity of copper-dependent metalloenzymes:
- Anemia -> dec. ceruloplasmin (iron oxidation)
- weakened bones -> dec. collagen cross-linking enzymes (lysyl oxidase)
- vascular dysfunction -> elastin cross-linking enzymes (lysyl oxidase)
- depigmentation of skin and hair -> dec. tyrosine activity - reduced synthesis of melanin
How are the population groups at risk for copper deficiency?
- Excessive intake of zinc, especially > 40mg/day (=UL of zinc)
- Chronic medication use, e.g., proton pump inhibitors reduced gastric acidity
- Diseases/conditions that promote copper losses e.g., nephrosis (kidney disease)
- Diseases/conditions that cause malabsorption
- Crohn’s disease
- short bowel syndrome
- celiac disease - Other diseases
- surgical bariatric procedures
What are the risks of excess copper intake?
Acute toxicity: abdominal pain, nausea, vomiting
- Chronic toxicity (rare): liver damage -> copper homeostasis; liver doesn’t catch up with amount of copper absorbed
What is the tolerable upper intake level (UL) for copper?
10,000 μg/day (10 mg/day)
for adults ≥19 years
What is the nutrient-nutrient interaction between zinc and copper?
- (Intestinal) metallothionein synthesis stimulated at high zinc intake
- Metallothionein has a higher affinity for copper
- Metallothionein binds to copper and reduces the flux of copper into the portal vein
- Zinc-induced copper deficiency
What is the nutrient-nutrient interaction between iron and copper?
- Low copper impairs iron transport
via reduced ceruloplasmin oxidase activity
What is the nutrient-nutrient interaction between vitamin C and copper?
Ascorbic acid maintains copper in appropriate oxidation state for enzyme function
Menke’s disease
ATP7A - copper deficiency
Physiological effects: Impaired release of copper from
enterocytes (↓ abs) → Copper deficiency. Impaired insertion of
Cu into enzymes & uptake of Cu by brain
Onset & Prognosis: Onset at birth
Poor prognosis with
life expectancy <10 years
Signs: Steely depigmented hair,
Ruptured arteries, Reduced BMD,
Brain & cognitive abnormalities
Treatment: None
Lab findings:
- inc. liver Cu
- dec. serum ceruloplasmin
dec. serum Cu ( inc. in acute liver failure)
Wilson’s Disease
ATP7B - copper toxicity
Physiological effects: Impaired excretion of copper in bile → Copper toxicity. Impaired secretion of ceruloplasmin
Onset & prognosis: Onset between 5-35 years with treatment normal &
healthy life
Signs: Liver disease, Impaired motor control and brain damage if untreated
Treatment: Chelating agents
Lab findings:
- dec. serum Cu
- dec. serum ceruloplasmin
- dec. liver Cu
- inc. intestinal Cu
