Molecular Mechanisms Of Human iron Distribution And Homeostasis Flashcards
Who does anemia mostly affect?
Young children
Pregnant and post-partpartum
Menstrutrating women
Which areas are most affected by anemia?
Lower to lower-middle income countries.
What percentage of children aged 6-59 months have been affected by anemia?
40%
What percentage of pregnant women have been affected by anaemia?
37%
What percentage of woman aged 15-49 are affected by anaemia?
30%
Where is iron associated?
Haem
Iron protein
Iron-Sulphur cluster
How is iron acquired from the diet?
Oxidation of ferrous iron in air forms insoluble ferric oxide-hydroxide species.
What iron compounds are in iron supplements?
Iron sulphide or chloride
Where does the haem form of iron come from?
Red meat
Where does the ferritin form of iron come from?
Pulses
What oxidation state is iron in its haem form?
+2
What oxidation state is iron in its ferritin form?
+3
What is the structure of ferritin?
24 protein cage with mineralized iron.
Is iron excreted?
No iron is recycled, excess is stored in the liver.
What is iron reuptake into the liver regulated by?
Enterocytes
Where does dietary iron go?
It is absorbed into the plasma where it is bound by a transferrin which transports it round the circulatory system.
How many grams of Iron are in the blood?
2.5-3g of iron are present in the blood.
Where does iron loss happen?
Skin shedding
Hair loss
Bleeding
What is Dcytb?
Iron reductase
What is DMT1?
Iron transporter
What is HCP1?
Haem transporter
What is HO1?
Haem oxygenase
What is FPN?
Ferroportin
Which form of iron is the soluble form?
Fe 2+
How is ferritin taken up into the serum?
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.
How is haem transported into the serum?
Transported in by HCP1.
Oxidised by HOP1.
Binds to ferroportin.
What is HPX?
Haemopexin
What is HP?
Haptoglobin
What is CP?
Ceruloplasmin
How is iron transported into the cell?
Bind to TFR1, transferrin receptor 1, this causes endocytosis of the complex into the cell.
What does the pH difference between the plasma and the cell do to the iron complex?
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.
How is iron recycled from red blood cells?
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.
What is HiF-2alpha?
Iron sensing protein
How does HiF-2alpha work in low iron?
Traffics to the nucleus from the cytosol and activate the transcriptions of iron transporters.
How does HiF-2alpha in high iron concentration?
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.
How can regulating mRNA regulate the concentration of iron?
IRP, iron reporter proteins.
What do IRP do in low iron concentration?
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.
What do IRP do in a high concentration of iron?
IRP are not bound to mRNA, so cannot hold iron in the cell.
How do IRP dissociate from mRNA?
Binding of a Fe-S cluster to the mRNA as the efficiency of binding is outcompeted in high concentrations of iron.
What happens to IPR association to mRNA when the concentration of iron is high but the concentration of oxygen is low?
Fe-S cluster are no longer as tightly bound and IPR can rebind.
Why is IPR rebinding in high concentrations of iron a problem?
Because unnecessary transcription is occurring.
How does the body combat IPR rebinding in low concentration of oxygen when iron is high?
FBXL5
What is FBXL5?
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)
What is ferroprotein regulated by?
Hepcidin
What is hepcidin?
A small peptide substrate which binds to ferroportin in high concentrations of iron.
What is the role of hepcidin in iron control?
It controls the release of iron in a variety of states.
Its presence prevents ferroportin shuffling the iron out of the cell.
What is the concentration of iron relative to hepcidin?
Negative linear
Where does Fe-TF, iron transferring bind?
TFR2 next to HFE
What does TFR2 HFE complex then signal the cell to do in high iron concentration?
Phosphorylate ERK1 and 2
What do ERK1 and 2 do after being phosphorylated?
Move into the nucleus and switch on the production of hepcidin.
What is the role of HFE in the complex?
Phosphorylates SMAD 1 5 and 8 which move into the nucleus and stabilise the production of hepcidin.
What is the main complex formation which leads to the phosphorylation of SMAD?
Bone marrow protein BMP6, which positively binds to receptor BMPR, and cofactor HJV which signals SMAD to be phosphorylated.
Why is cofactor HJV present in high iron concentration?
FE-TF transferrin, prevents it from being cleaved off the cell surface.
Where is HFE in a low iron concentration?
Next to TFR1 leaving 2 vacant.
What happens to HJV in low iron concentration?
It is degraded by enzyme matriptase-2, stops complex forming and therefore the production of hepcidin.
Furin cleaves HJV.
What is haemochromatosis?
Disorder of iron absorption and storage within the body.
Characteristic pattern of tissue damage from excess iron deposition.
How common is hemochromatosis?
Most common inherited metabolic disorder in the Western World.
1 in 250
What is the clinical presentation of haemochromatosis?
Cirrhosis
Diabetes
Skin discolouration
Lethargy
How is haemochromatosis diagnosed?
Serum ferritin concentration accurately reflects total body iron stores and is raised in the disease.
Magnetic resonance of the liver.
What are the treatment for haemochromatosis?
Regular phlebotomy to low iron stores.
Deferoxamine as an iron chelator.
How does life expectancy change when the individual has hemochromatosis?
Normal if treated before the development of diabetes or cirrhosis.
What is the mechanism of haemochromatosis?
Hepcidin levels are low due to mutations in: HFE, HJV, Hepcidin, Transferrin receptor 2, Ferroportin.
