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FNH 351 > Copper > Flashcards

Copper Flashcards

1
Q

What are the chemical forms of copper?

A

esstenial micromineral

Cu2+ (cupric)
Cu+ (cuprous)

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2
Q

What is the enzymatic function of copper?

A

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

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3
Q

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

A
  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
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4
Q

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

A

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

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5
Q

What is copper’s function in iron transport?

A

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

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6
Q

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

A

Cytochrome c oxidase = terminal oxidation step in electron transport chain

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7
Q

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

A

Melanin production pathway - cofactor for the enzyme tyrosinase

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8
Q

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

A

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

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9
Q

What is copper’s function in hormone activation?

A

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

Hormones includes gastrin, cholecystokinin, calcitonin, thyrotropin, vasopressin

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10
Q

What is copper’s function in neurological roles?

A

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

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11
Q

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:

A

Vitamin C

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12
Q

What are natural food sources of copper?

A

Legumes; nuts and seeds; organ meats; shellfish

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13
Q

What is the form of copper in foods?

A

Cu2+ (cupric) bound to amino acids/proteins

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14
Q

How is copper digested in the body?

A

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)

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15
Q

How is it absorbed in the enterocyte?

A

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

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16
Q

What is the overall absorption rate?

A

Absorption efficiency inversely related to dietary intakes and body copper status

17
Q

What are enhancers of copper bioavailability?

A
  • Amino acids (His, Cys); glutathione (contains Cys)
  • Organic acids (e.g., citric acid, acetic acid)
  • Higher acidity (i.e., low pH)
18
Q

What are inhibtors of copper bioavailability?

A
  • Phytic acid
  • Other divalent cations (e.g., Zn, possibly Fe)
  • Increased pH
    Antacid -> increase in pH -> insolubility -> impaired absorption
19
Q

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

A

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

20
Q

How is copper transported from the intestine to the liver?

A

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

21
Q

How is copper metabolized in liver cells (hepatic)?

A

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

22
Q

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

A

Binding of copper by chaperone proteins pro-oxidant effects

23
Q

What is the key role of ATP7A?

A
  • Transport of copper through basolateral membrane of enterocyte
  • Release of copper from most cells (except liver)
  • Transport of copper across blood-brain barrier
24
Q

What is the key role of ATP7A?

A
  • Transport of copper into Golgi for synthesis of copper-containing enzymes & ceruloplasmin
  • Export of copper into bile duct for excretion
25
Q

How is copper transported to extrahepatic tissues in plasma?

A

Ceruloplasmin secreted from liver contains 60%-70% of circulating copper in blood

Remaining copper circulates loosely bound to albumin to other proteins

26
Q

How is copper cellular uptaken, transported and metabolized?

A

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)

27
Q

Where does copper homeostasis occur?

A

Liver = main site for Cu storage and controlling copper homeostasis

28
Q

How is copper stored?

A
  • 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
29
Q

How is copper excreted?

A

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

30
Q

What are the health implications of deficiency?

A

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

31
Q

What are copper deficiency symptoms?

A

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

32
Q

How are the population groups at risk for copper deficiency?

A
  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
33
Q

What are the risks of excess copper intake?

A

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

34
Q

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

A

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

35
Q

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

A
  • (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
36
Q

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

A
  • Low copper impairs iron transport
    via reduced ceruloplasmin oxidase activity
37
Q

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

A

Ascorbic acid maintains copper in appropriate oxidation state for enzyme function

38
Q

Menke’s disease

A

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)

39
Q

Wilson’s Disease

A

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

FNH 351 (6 decks)

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