Copper

Question 1

What are the chemical forms of copper?

Answer 1

esstenial micromineral

Cu2+ (cupric)
Cu+ (cuprous)

Question 2

What is the enzymatic function of copper?

Answer 2

Cofactor of metalloenzymes:
- participates at the catalytic site or allosteric site
- involved in oxidation-reduction reactions

Question 3

How does copper serve as a cofactor in oxidation-reduction reactions?

Answer 3

1. Antioxidant function: Cu/Zn superoxide dismutase (SOD)
2. Iron transport: Ceruloplasmin and hephaestin
3. Electron transport chain
4. Pigment (melanin) synthesis: tyrosinase
5. Collagen synthesis (in lysyl oxidase)
6. Hormone activation
7. Neurological roles

Question 4

What is copper’s role in Cu/Zn superoxide mutase (SOD)?

Answer 4

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

Question 5

What is copper’s function in iron transport?

Answer 5

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

Question 6

What is copper’s function in the electron transport chain?

Answer 6

Cytochrome c oxidase = terminal oxidation step in electron transport chain

Question 7

What is copper’s function in pigment (melanin) synthesis?

Answer 7

Melanin production pathway - cofactor for the enzyme tyrosinase

Question 8

What is copper’s function in collagen & elastin synthesis (vis lysyl oxidase?

Answer 8

Copper is required for lysyl oxidase - cross-linking of tissue proteins for the assembly into fibrils

Question 9

What is copper’s function in hormone activation?

Answer 9

Cu required for amidation of peptides hormones -> critical for hormone function

Hormones includes gastrin, cholecystokinin, calcitonin, thyrotropin, vasopressin

Question 10

What is copper’s function in neurological roles?

Answer 10

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

Question 11

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:

Answer 11

Vitamin C

Question 12

What are natural food sources of copper?

Answer 12

Legumes; nuts and seeds; organ meats; shellfish

Question 13

What is the form of copper in foods?

Answer 13

Cu2+ (cupric) bound to amino acids/proteins

Question 14

How is copper digested in the body?

Answer 14

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)

Question 15

How is it absorbed in the enterocyte?

Answer 15

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

Question 16

What is the overall absorption rate?

Answer 16

Absorption efficiency inversely related to dietary intakes and body copper status

Question 17

What are enhancers of copper bioavailability?

Answer 17

• Amino acids (His, Cys); glutathione (contains Cys)
• Organic acids (e.g., citric acid, acetic acid)
• Higher acidity (i.e., low pH)

Question 18

What are inhibtors of copper bioavailability?

Answer 18

• Phytic acid
• Other divalent cations (e.g., Zn, possibly Fe)
• Increased pH
  Antacid -> increase in pH -> insolubility -> impaired absorption

Question 19

What are the 3 possible fates of absorbed copper in enterocytes?

Answer 19

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

Question 20

How is copper transported from the intestine to the liver?

Answer 20

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

Question 21

How is copper metabolized in liver cells (hepatic)?

Answer 21

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

Question 22

What is the main role of chaperone proteins in the intracellular movement of copper?

Answer 22

Binding of copper by chaperone proteins pro-oxidant effects

Question 23

What is the key role of ATP7A?

Answer 23

• Transport of copper through basolateral membrane of enterocyte
• Release of copper from most cells (except liver)
• Transport of copper across blood-brain barrier

Question 24

What is the key role of ATP7A?

Answer 24

• Transport of copper into Golgi for synthesis of copper-containing enzymes & ceruloplasmin
• Export of copper into bile duct for excretion

Question 25

How is copper transported to extrahepatic tissues in plasma?

Answer 25

Ceruloplasmin secreted from liver contains 60%-70% of circulating copper in blood Remaining copper circulates loosely bound to albumin to other proteins

Question 26

How is copper cellular uptaken, transported and metabolized?

Answer 26

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)

Question 27

Where does copper homeostasis occur?

Answer 27

Liver = main site for Cu storage and controlling copper homeostasis

Question 28

How is copper stored?

Answer 28

* 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

Question 29

How is copper excreted?

Answer 29

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

Question 30

What are the health implications of deficiency?

Answer 30

Rare in adults = more likely with high Zn intake or meds that reduce Cu absorption

Question 31

What are copper deficiency symptoms?

Answer 31

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

Question 32

How are the population groups at risk for copper deficiency?

Answer 32

1. Excessive intake of zinc, especially > 40mg/day (=UL of zinc) 2. Chronic medication use, e.g., proton pump inhibitors reduced gastric acidity 3. Diseases/conditions that promote copper losses e.g., nephrosis (kidney disease) 4. Diseases/conditions that cause malabsorption - Crohn’s disease - short bowel syndrome - celiac disease 5. Other diseases - surgical bariatric procedures

Question 33

What are the risks of excess copper intake?

Answer 33

Acute toxicity: abdominal pain, nausea, vomiting - Chronic toxicity (rare): liver damage -> copper homeostasis; liver doesn't catch up with amount of copper absorbed

Question 34

What is the tolerable upper intake level (UL) for copper?

Answer 34

10,000 μg/day (10 mg/day) for adults ≥19 years

Question 35

What is the nutrient-nutrient interaction between zinc and copper?

Answer 35

- (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

Question 36

What is the nutrient-nutrient interaction between iron and copper?

Answer 36

- Low copper impairs iron transport via reduced ceruloplasmin oxidase activity

Question 37

What is the nutrient-nutrient interaction between vitamin C and copper?

Answer 37

Ascorbic acid maintains copper in appropriate oxidation state for enzyme function

Question 38

Menke's disease

Answer 38

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)

Question 39

Wilson's Disease

Answer 39

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