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Chronic Disease > Molecular Mechanisms Of Human iron Distribution And Homeostasis > Flashcards

Molecular Mechanisms Of Human iron Distribution And Homeostasis Flashcards

1
Q

Who does anemia mostly affect?

A

Young children

Pregnant and post-partpartum

Menstrutrating women

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2
Q

Which areas are most affected by anemia?

A

Lower to lower-middle income countries.

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3
Q

What percentage of children aged 6-59 months have been affected by anemia?

A

40%

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4
Q

What percentage of pregnant women have been affected by anaemia?

A

37%

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5
Q

What percentage of woman aged 15-49 are affected by anaemia?

A

30%

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6
Q

Where is iron associated?

A

Haem

Iron protein

Iron-Sulphur cluster

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7
Q

How is iron acquired from the diet?

A

Oxidation of ferrous iron in air forms insoluble ferric oxide-hydroxide species.

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8
Q

What iron compounds are in iron supplements?

A

Iron sulphide or chloride

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9
Q

Where does the haem form of iron come from?

A

Red meat

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10
Q

Where does the ferritin form of iron come from?

A

Pulses

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11
Q

What oxidation state is iron in its haem form?

A

+2

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12
Q

What oxidation state is iron in its ferritin form?

A

+3

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13
Q

What is the structure of ferritin?

A

24 protein cage with mineralized iron.

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14
Q

Is iron excreted?

A

No iron is recycled, excess is stored in the liver.

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15
Q

What is iron reuptake into the liver regulated by?

A

Enterocytes

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16
Q

Where does dietary iron go?

A

It is absorbed into the plasma where it is bound by a transferrin which transports it round the circulatory system.

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17
Q

How many grams of Iron are in the blood?

A

2.5-3g of iron are present in the blood.

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18
Q

Where does iron loss happen?

A

Skin shedding
Hair loss
Bleeding

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19
Q

What is Dcytb?

A

Iron reductase

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20
Q

What is DMT1?

A

Iron transporter

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21
Q

What is HCP1?

A

Haem transporter

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22
Q

What is HO1?

A

Haem oxygenase

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23
Q

What is FPN?

A

Ferroportin

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24
Q

Which form of iron is the soluble form?

A

Fe 2+

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25
Q

How is ferritin taken up into the serum?

A

Reduced to 2+, transported into enterocytes, once inside it can either move toward ferritin and bind and be stored inside the cell or moved towards ferroprotin which exports it out. Converted back to 3+ which binds to transferrin.

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26
Q

How is haem transported into the serum?

A

Transported in by HCP1.

Oxidised by HOP1.

Binds to ferroportin.

27
Q

What is HPX?

A

Haemopexin

28
Q

What is HP?

A

Haptoglobin

29
Q

What is CP?

A

Ceruloplasmin

30
Q

How is iron transported into the cell?

A

Bind to TFR1, transferrin receptor 1, this causes endocytosis of the complex into the cell.

31
Q

What does the pH difference between the plasma and the cell do to the iron complex?

A

When the iron complex is endocytosed by the cell it is in an endosomal which have a pH of 6.2.

This makes the iron oxidised to +3 which is insoluble.

STEEP3 reduces it back to iron +2

Iron is then transported out of the endosomal.

32
Q

How is iron recycled from red blood cells?

A

When iron is released it is in the 2+ state which is redox active.

This then oxidised by CP to give 3+

This can then be bound to transferrin.

33
Q

What is HiF-2alpha?

A

Iron sensing protein

34
Q

How does HiF-2alpha work in low iron?

A

Traffics to the nucleus from the cytosol and activate the transcriptions of iron transporters.

35
Q

How does HiF-2alpha in high iron concentration?

A

Produce proteins called PHDs, they bind to HiF-2alpha and prevent its translocation which prevents production f iron transporters and targeted degradation by hydroxylation and ubiquitination, signals to the cell that the HiF protein needs to be turned off.

36
Q

How can regulating mRNA regulate the concentration of iron?

A

IRP, iron reporter proteins.

37
Q

What do IRP do in low iron concentration?

A

Block ferroprotein transporter and the production of ferratin as well as the storage.

Stabile DMT1 transporter.

Degrade HiF-2alpha.

This blocks the export of iron and keeps it in the cell.

38
Q

What do IRP do in a high concentration of iron?

A

IRP are not bound to mRNA, so cannot hold iron in the cell.

39
Q

How do IRP dissociate from mRNA?

A

Binding of a Fe-S cluster to the mRNA as the efficiency of binding is outcompeted in high concentrations of iron.

40
Q

What happens to IPR association to mRNA when the concentration of iron is high but the concentration of oxygen is low?

A

Fe-S cluster are no longer as tightly bound and IPR can rebind.

41
Q

Why is IPR rebinding in high concentrations of iron a problem?

A

Because unnecessary transcription is occurring.

42
Q

How does the body combat IPR rebinding in low concentration of oxygen when iron is high?

A

FBXL5

43
Q

What is FBXL5?

A

Iron oxide dimer complex which forms in high iron concetration that targets IRP for degradation by the proteasome.

In a hypoxic environment it outcompetes the mRNA for binding.

(When in the presence of other proteins)

44
Q

What is ferroprotein regulated by?

A

Hepcidin

45
Q

What is hepcidin?

A

A small peptide substrate which binds to ferroportin in high concentrations of iron.

46
Q

What is the role of hepcidin in iron control?

A

It controls the release of iron in a variety of states.

Its presence prevents ferroportin shuffling the iron out of the cell.

47
Q

What is the concentration of iron relative to hepcidin?

A

Negative linear

48
Q

Where does Fe-TF, iron transferring bind?

A

TFR2 next to HFE

49
Q

What does TFR2 HFE complex then signal the cell to do in high iron concentration?

A

Phosphorylate ERK1 and 2

50
Q

What do ERK1 and 2 do after being phosphorylated?

A

Move into the nucleus and switch on the production of hepcidin.

51
Q

What is the role of HFE in the complex?

A

Phosphorylates SMAD 1 5 and 8 which move into the nucleus and stabilise the production of hepcidin.

52
Q

What is the main complex formation which leads to the phosphorylation of SMAD?

A

Bone marrow protein BMP6, which positively binds to receptor BMPR, and cofactor HJV which signals SMAD to be phosphorylated.

53
Q

Why is cofactor HJV present in high iron concentration?

A

FE-TF transferrin, prevents it from being cleaved off the cell surface.

54
Q

Where is HFE in a low iron concentration?

A

Next to TFR1 leaving 2 vacant.

55
Q

What happens to HJV in low iron concentration?

A

It is degraded by enzyme matriptase-2, stops complex forming and therefore the production of hepcidin.

Furin cleaves HJV.

56
Q

What is haemochromatosis?

A

Disorder of iron absorption and storage within the body.

Characteristic pattern of tissue damage from excess iron deposition.

57
Q

How common is hemochromatosis?

A

Most common inherited metabolic disorder in the Western World.

1 in 250

58
Q

What is the clinical presentation of haemochromatosis?

A

Cirrhosis

Diabetes

Skin discolouration

Lethargy

59
Q

How is haemochromatosis diagnosed?

A

Serum ferritin concentration accurately reflects total body iron stores and is raised in the disease.

Magnetic resonance of the liver.

60
Q

What are the treatment for haemochromatosis?

A

Regular phlebotomy to low iron stores.

Deferoxamine as an iron chelator.

61
Q

How does life expectancy change when the individual has hemochromatosis?

A

Normal if treated before the development of diabetes or cirrhosis.

62
Q

What is the mechanism of haemochromatosis?

A

Hepcidin levels are low due to mutations in: HFE, HJV, Hepcidin, Transferrin receptor 2, Ferroportin.

63
Q
A

Chronic Disease (15 decks)

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