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Molecular Basis Of Disease > Trace Elements (Iron and Zinc) > Flashcards

Trace Elements (Iron and Zinc) Flashcards

1
Q

Growth studies on animals with deficiency in copper and cobalt caused what

A

Copper
- steely wool
- ataxia
- swayback

cobalt
- reduced vitamin B12 synthesis
- wasting

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2
Q

How much iron is needed daily and how much of this amount is actually absorbed

A

about 10-20 mg

10-15% of this amount is absorbed mainly through the duodenum

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3
Q

What food are rich in iron

A

meats
nuts
green vegetables
seafood

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4
Q

Where is Iron stored in the body

A

60-70%
- haemoglobin
- 2.5 g Fe in RBC

5-15%
- other hemoproteins (cytochrome c, catalase, myoglobin)
- other protein groups which contain Fe (iron-sulfur proteins, NADH dehydrogenase)

10-20%
- ferritin (and hemosiderin) in hepatocytes and reticuloendothelial macrophages
- transferrin: Fe transport in blood

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5
Q

What is Ferritin

A

Ferritin is a protein which stores Iron in cells in a soluble and non toxic form

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6
Q

Why is it best for Iron to be in soluble form

A

Free Fe can be used to induce the Fenton reaction which creates free radicals

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7
Q

What is Ferritin known as when it is not bound to iron

A

apoferritin

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8
Q

What is hemosiderin and what is its function

A

hemosiderin a complex of:
- denatured ferritin
- lysosomes
- and other material

function:
When RBC’s are broken down the iron is recycled and temporarily stored in hemosiderin

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9
Q

Red blood cells become fragile about 100-120 days and are broken down by macrophages in the spleen, live and other tissues. What happens to the heme in these RBC’s

A

heme is liberated and returned to the plasma and the iron is recycled and stored in hemosiderin.

Some heme is then broken down in the liver into bilirubin which is then excreted into the bile through the intestines then into the faeces

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10
Q

1-2 mg of Iron in the body is lost through

A

bleeding (e.g. menstruation)
sweating
lactation
damage to intestinal mucosa (e.g. desquamation of epithelial cells in gastrointestinal tract)

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11
Q

Where is iron found in the body (from most to least amount)

A
  1. red blood cell
  2. macrophages
  3. muscle fibres
  4. Liver
  5. bone marrow
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12
Q

What are the 3 forms of dietary iron and which is the most stable

A

ferrous iron (Fe2+)

ferric iron (Fe3+)
- most stable
- non-heme iron
- mostly found in plant sources

heme iron (Fe2+ chelated as hemoglobin, myoglobin and enzymes)
- mostly found in meat sources

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13
Q

Which form of iron is found in the cell and which form in the blood and why does this differ?

A

Fe2+ in cell
- iron needs to be in the cell in the most reduced form

Fe3+ in blood
- most stable

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14
Q

When Fe2+ (non heme) enters the cell what are the two outcomes that can occur?

A
  1. stored in ferritin
  2. pass through the basolateral membrane to reach the blood and enter circulation
    - Fe2+ is re-oxidized by a ferroxidase (plasma ferroxidase ceruloplasmin or hephaestin) to form Fe3+
    - then transported through ferroportin (a membrane Fe2+ exporter)
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15
Q

Once Fe3+ exits the duodenal enterocyte through ferroportin it attaches to what

A

bound to transferrin

transferrin without iron bound = apotransferrin
transferrin with bound iron = holo-transferrin

transferrin usually circulates in plasma serum

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16
Q

How is heme iron transported into duodenal epithelial cells

A
  1. heme iron is transported across the apical membrane by heme carrier protein 1
  2. once inside Hox1 (heme oxygenase) breaks heme and removes iron
  3. Fe2+ is now non heme and can undergo with stroage and exit
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17
Q

How is non heme iron transported into cells

A

through the DMT1 (divalent metal transporter 1)

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18
Q

Once iron is bound to transferrin (halo-transferrin) how does is it taken up

A
  1. halo-transferrin binds to transferrin receptor on cell membrane
    - through endocytosis it is taken into the cell into endosomes
  2. Fe3+ dissociates from transferrin in endosome
  3. Fe3+ transported out of endosome into cytosol by DMT1
  4. iron is then either stored or utilised by cell
  5. endosome then combines with PM to release Apo transferrin into plasma again
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19
Q

Iron deficiency can be caused by 3 different things

A
  1. diet
  2. bleeding
  3. genetic disorders (rare)
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20
Q

What is the main result of iron deficiency

A

anaemia (a decrease in the number of erythrocytes)
- causes: weakness and fatigue
- severe cases: cardiac abnormalities

type of anemia: microcytic anaemia
- smaller RBC’s with much less haemoglobin
- decreased capacity for oxygen transport

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21
Q

When iron deficient where is iron depleted first

A

skeletal muscle and intestinal mucosa is depleted before heart and liver iron

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22
Q

What is the first line of treatment for iron deficiency

A

iron supplementation

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23
Q

Iron toxicity can be ……… or ………..

A

acquired or genetic

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24
Q

what is the molecular basis of acquired iron toxicity

A

linked to polymorphisms in ferroportin gene is associated with higher ferritin levels (higher storage of iron)

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25
Q

What are the symptoms of acquired iron toxicity

A

cell damage in:
- liver
- heart
- pancreas

increased incidence of liver cancer and cirrhosis

skin become a pigmented (a bronze golden colour)

26
Q

What does genetic iron toxicity cause

A

hemochromatosis (increased absorption of iron)
- 5 identified types with different mutations in the HFE gene

27
Q

Hemochromatosis symptoms

A

chronic fatigue
accumulation of iron
joint pain and arthritis
‘bronze’ diabetes:
- accumulation of iron in pancreas Beta cells (reduces/stops insulin secretion)

28
Q

What is the molecular basis of hereditary hemochromatosis (Type 1)

A

common mutation: C282Y (83% of cases)

HFE binds to transferrin receptor to regulate iron uptake
- mutated HFE signals LOW iron constantly therefore body is constantly uptaking iron

HFE also regulated production of hepcidin
- hepcidin determines how much iron is absorbed from diet and released from storage

29
Q

Treatment of hemochromatosis

A

phlebotomy (bloodletting)
- withdrawal of large quantities of blood

desferrioxamine mesilate
- iron chelating compound

30
Q

What is a chelating compound

A

chemical compound which reacts with metal compounds to form stable, water soluble metal complexes so it can be excreted

31
Q

What is the function of zinc

A
  • needed for the function of over 200 enzymes
  • forms complexes with other molecules
  • involved in structural, catalytic and co-catalytic enzymes
  • involved in DNA binding proteins
32
Q

What is the function of carbonic anhydrase enzyme and how is zinc incorporated into the enzyme

A

function:
- regulates CO2 in the cell by converting it to bicarbonate and hydrogen ion

its active sites contain a zinc ion

*******note: enzymes with a metal incorporated = metalloenzymes

33
Q

What is a zinc finger? what are its functions

A

small protein structural motif which can require one or more zinc ions to stabilized protein folds in mostly transcription factors

34
Q

What are the roles of zinc in nucleic acid metabolism

A
  1. DNA synthesis and transcription
  2. gene regulation
35
Q

What are the roles of zinc in signalling pathways

A
  1. regulates activity of cAMP and cGMP
  2. activates protein kinase C
  3. affects NMDA and GABA receptor activity
  4. releases calcium from intracellular stores in hepatocytes
36
Q

What are the roles of zinc in the extracellular matrix

A
  1. required for activity of matrix metalloproteinases
37
Q

What are the roles of zinc in membrane function

A
  1. required for membrane stability

******* note: zinz is also involved in lipid metabolism

38
Q

How does zinc influence synaptic function of neurons

A
  1. zinc is released from the presynaptic neuron and can act on many receptors on the postsynaptic neuron
    - they can inhibit or potentiate a few different receptors
    - it can specifically inhibit EAAT-1 (glutamate transporter) on glial cells therefore increasing glutamates action on the postsynaptic membrane
  2. Zinc can also alter signal transduction pathways which may affect cellular responses and protein synthesis
    - e.g. PKC cAMP
39
Q

How is zinc stored and released in neurons

A

stored in: vesicles in presynaptic neuron

released: at the synapse to modulate signal transduction pathway (neuromodulators)

40
Q

How does Zinc cause brain cell death in brain injury (e.g. stroke)/ zinc deficiency

A
  1. cytosolic free zinc is increased in apoptotic neurons (damaged neurons from trauma) which accumulates during apoptosis
  2. this leads to zinc being released into extracellular environment leading to more cell death in adjacent neurons
41
Q

How is neuronal death caused by zinc treated

A

zinc chelators
- these bind to zinc limiting to toxicity

42
Q

How much zinc is required per day and what is the total zinc content in the body

A

about 10 mg is needed per day

total zinc content in body = 1-2 grams

43
Q

What is the distribution of zinc in parts of the body

A

85-95%:
- muscle
- bone
- hair
- skin

about 30%:
- skeletal muscle

44
Q

Where is the largest concentrations of zinc in the human body

A
  1. retina
  2. prostate gland
  3. ECM
45
Q

What is the plasma concentration of zinc

A

11-22 mM (0.1% total body zinc)
- bound to albumin in blood

46
Q

What are the 2 causes of zinc deficiency

A
  1. nutritional
  2. inherited
47
Q

What are the symptoms of nutritional zinc deficiency

A

growth retardation
loss of appetite (anorexia)
impaired immune function

severe cases:
hair loss, diarrhoea, delayed sexual maturation, impotence, hypogonadism in males, eye and skin lesions, alopecia, depression, impaired taste

48
Q

What is inherited zinc deficiency known as and what is the most common cause

A

acrodermatitis enteropathica
- transient neonatal zinc deficiency

cause: mother not having enough zinc in diet when pregnant causing the baby to be born deficient

49
Q

What conditions can predispose individuals to nutritional zinc deficiency

A
  1. inadequate intake/absorption of zinc
    - inflammatory bowel disease, biliary obstruction, liver disease, renal failure
  2. malnutrition
  3. vegetarianism with poor diet
  4. therapeutic and synthetic diets
    - enteral and parenteral nutrition, diets for management of inborn errors of metabolism
  5. intestinal infestation (bacteria, worms etc)
  6. nutritional interactions with dietary components and drugs
    - diuretics and antibiotics
50
Q

What is the genetic basis of acrodermatitis enteropathica and when do symptoms usually occur

A

autosomal recessive disorder
- mutations in SLC39A4 a zinc uptake transmembrane protein

symptoms usually occur:
1. bottle fed infants = a few days or weeks after birth
2. breast fed infants = soon after weaning
- zinc deficiency in premature breastfed babies due to
reduced zinc levels of mothers milk

51
Q

What symptoms is inherited zinc deficiency characterised by

A

skin inflammation (dermatitis)
- usually around mouth and anus
diarrhoea
hair loss (alopecia)
malabsorption of zinc through intestinal cells

52
Q

Zinc transporters can be located in which 2 locations

A
  1. plasma membrane
  2. intracellular membranes
53
Q

what are the 2 main families of zinc transporters

A
  1. solute carrier 30 (SLC30) = ZnT
  2. solute carrier 39 (SLC39) = ZIP
54
Q

what is the function of Zinc transporter ZnT

A
  1. zinc ions from cytoplasm out of the cell (efflux)
  2. zinc from cytoplasm into vesicles
55
Q

What is the function of zinc transporter ZIP

A
  1. zinc ions from outside of the cell into cytoplasm
  2. zinc from vesicles into cytoplasm
56
Q

What is the structure of zinc transporter ZIP

A

pairs to form homodimers
- has intracellular loops with no known functions

57
Q

What is the structure of zinc transporter ZnT

A

contains many loops which contain leucine and histidine amino acids
- zinc binds to these to be transported from cytosol into vesicles/ organelles

58
Q

Do the two different zinc transporters co-localise

A

no found in different areas of cell membrane

59
Q

Taking zinc supplementation can reduce what?

A
  1. duration and severity of diarrhoea in malnourished children
  2. duration and severity of common cold
  3. may prevent macular degeneration
60
Q

What are the symptoms of zinc toxicity

A

nausea and vomiting
gastric and esophageal bleeding
dizziness
lethargy
fever
copper deficiency
- metallothionein binding in enterocytes have competitive binding to copper
anaemia
metal fume fever
- welders exposed to zinc oxide forms
- causes flu like symptoms

61
Q

ZINC TOXICITY CASE STUDY:
38 year old schizophrenic man with metal PICA presented with asymptomatic anaemia. 275 coins surgically removed made primarily of zinc. What were his other symptoms?

A

coins showed severe corrosion from prolonged contact with gastric juice

symptoms consistent with systemic effects of zinc toxicity

Molecular Basis Of Disease (17 decks)

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