Fe is always transported or stored as Fe(ferric) b/c unbound Fe can generate highly reactive

FREE RADICALS

Can cause tissue damage(HO-)

1) When does Fe absorption increase?

2) How is Fe homeostatasis tightly controlled?

1) absorption increases when Fe stores are LOW

2)Fe is recycled within body and absorption is regulated

1) Heme Fe are taken into cell where/how?

2) What is it degraded into what and releasing what?

1) taken up on the luminal surface of enterocyte (mucosal cell)

Heme Fe is taken up intact

2) degraded to bilirubin releasing Fe into enterocyte

1) How are non-heme Fe absorbed?

2) non-heme Fe is bound to what before absorbed into enterocyte?

1) DMT1

2) mucin

1) When Fe is released from either non-heme or heme what does it bind?

2) What is the function of this protein?

1) Fe w/in enterocyte binds MOBILFERRIN

2) transports Fe thru the enterocyte

1) Where does Fe exit the cell and by what?

2) What does Ferroportin function in?

1) Fe exits the basolateral surface of cell via a membrane iron carrier

 FERROPORTIN

2) Ferroportin functions in Fe absorption and Fe recycling

1) What controls the amount of Fe available to transferrin?

2) What controls the levels of ferroportin?

1) hepcidin

2) hepcidin

1) How does hepcidin function?

2) What does hepcidin prevent?

3) The amount of hepcidin produced by liver changes in response to what?

1) by binding FERROPORTIN inducing internalization and degradation

2) hepcidin prevents release of Fe from cells

3) inflammation, high [Fe], hypoxia, anemia

1) Low levels of hepcidin results in what?

2) high levels of hepcidin results in what?

1) low hepcidin results in high ferroportin which results in release of Fe to transferrin so

increased iron absorption

2) high hepcidin results in decreased levels of ferroportin, preventing transcellular Fe transport

so decreased Fe absorption

When hepcidin prevents release of Fe from cells what does Fe bind to and what happens to it?

1) What causes hypoferremia?

2) What does hypoferremia limit?

3) During this situation what is not released?

4) In chronic situations what can Hypoferremia causes?

1) In acute infection IL-6 triggers liver to release hepcidin

2) limits bacterial growth and hydroxyl radical form. b/c low Fe

3) Fe is not released from macrophage for distribution to bone marrow for Hb syn

4) hypoferremia can result in ANEMIA

1) What does lactoferrin play a role in?

2) What is lactoferrin similar to in structure and function?

3) What is Lactoferrin synthesized by?

1) hypoferremia

2) similar to transferrin in structure and function by being a bld transport protein

3) neutrophils during inflammation and infection 

1) what does hephaestin do?

1) converts Fe² to Fe³

^{"safe form"}

-Transferrin binds Fe tightly,

-has 2 binding sites for Fe3+

1) What is apotransferrin?

2) What does apotransferrin do?

3) Where does this apotransferrin transport Fe to?

1) empty transferrin

2) binds Fe3+ at enterocyte or from internal stores 

3) transports Fe to all growing cells

1) What does TfR mediate?

2) Where is TfR abundant?

3) How does TfR function?

4) When does TfR release Fe?

5) What is returned to ECF and plasma membrane?

1) mediates cellular uptake of Fe-transferrin

2) hepatocytes, immature erythrocytes, malg/non malignant rapidly dividing cells

3) TfR endocytoses TFR transferrin-Fe complex creating an endosome

4) TfR releases Fe as endosome is acidified

5) apotransferrin and TfR

1) when does TfR-1 bind Fe-transferrin?

2) what kind of coat forms around pit?

3) At what ph is Fe released from transferrin?

4) What pumps Fe to cytosol?

5) what happens to TfR-1-apo-transferrin complexes?

1) TfR-1 binds Fe-transferrin at physiological ph

2) clathrin coated pit

3) endosomal acidification happens at 5-5.5 ph

4) DMT1 pumps Fe from endosome to cytosol

5) the complexes recycled to cell membrane and dissociate at physiological ph (6)

1) How does IRP and IRE regulate TfR expression?

1) when IRE binds IRP in low [Fe] it stabilizes mRNA and TfR are made

2) When [Fe] is high IRP binds Fe so nothing binds IRE so TfR mRNA degraded 

When [Fe] low, IRP binds IRE on 5' UTR of ferritin mRNA----decreasing ferritin levels

When [Fe] high, IRP binds Fe causing conformation change so it no longer binds IRE so translation of ferritin mRNA cont

1) What has to happen to form heme?

2) What is heme controlled by?

3) What is the rate-limiting step and what two isoenzymes is there?

1) Fe must be inserted into the porphyrin ring to form heme

2) syn of heme is controlled by [Fe] & [heme]

3) rate limiting step is syn of enzyme of ALA-S,

ALA-S1-cytochrome syn

ALA-S2-hemoglobin syn

1) transcription of ALA-S1 gene

2) translation of ALA-S1 mRNA

3) translocation of ALA-S1 into mito

1) Is heme an allosteric effector for ALA-S1?

2) A decrease in heme causes what?

1) NO

2) 50x increase in [ALA-S1]

ALA-S1 has short half-life

What happens in Loop 1 of Coordinate Regulation?

1) Loop 2

2) Does loop 2 inhibit transcription of ALA-S2 as with ALA-S1?

1) Heme inhibits Fe uptake of Fe-transferrin complex

2) NO it does not inhibit transcription

Loop 4: How does heme regulate globin translation?

2) does this affect all translation during reticulocytosis?

Absence of heme activates heme-kinase which phosphorylates the alpha subunit of eIF-2 in erythrocytes causing decreased globin syn

2) yes activity of eIF2 HCl kinase affects all translation