EXAM #1: IRON HEMOSTASIS & PORPHYRIN METABOLISM Flashcards
What is the typical daily iron requirement from the diet?
10-20mg
*****Note that this comes from heme in animal products, and non-heme (Fe+++) from vegetables.
What patient populations have an increased iron need?
1) Menstruating women
2) Pregnant women
3) Growing children
**Note that there may be increased need in vegetarians b/c non-heme iron is not easily absorbed*
Why is iron complexed with proteins and biomolecules in the body?
Free Fe++ and Fe+++ would generate damaging ROS
Note that Fe+++ is NOT biologically useful and is reduced by RBCs back to Fe++. Oxidation of Fe++ to Fe+++ produces hydroxide radical and superoxide anion
What are the functional forms of iron?
1) Hb
2) Myoglobin
3) Cytochromes
4) Other iron containing enzymes
What are the two storage forms of iron?
Ferritin
Hemosiderin
What is Ferritin?
Storage molecule from which iron is released on demand
What is hemosiderin?
Degenerated iron/protein complex that cannot be metabolized
Clinically, what is hemosiderin in tissues an indication of?
Iron overload
What cells in the body take-up iron?
Enterocytes in the proximal duodenum
What is the role of transferrin in the body?
Binds iron in the plasma for transport
Once iron is in the plasma, what happens to it?
Travels to the bone marrow and is incorporated into RBCs
When is iron stored as ferretin?
Once it has been phagoctosed by splenic macrophages
When iron is released from macrophages on demand, how is it transported?
As transferrin in plasma
What organ stores ferretin iron aside from splenic macrophages?
Liver stores ferretin
How is iron homeostasis regulated?
Iron UPTAKE is regulated at the level of the ENTEROCYTES
Can iron be excreted from the body?
NO
Iron only leaves the body from bleeding or sloughing off of duodenal enterocytes
How is heme iron taken up into the body via enterocytes?
Heme Carrier Protein 1
i.e. HCP-1
How is non-heme (Fe+++) iron absorbed?
1) Reduction by enterocyte cytochromep450
2) Uptake by divalent metal transporter (DMT-1)
What is the function of ferroportin?
Transporter that releases Fe++ iron from the enterocytes into the plasma
What regulates whether iron stays in the enterocyte or is transported into the plasma?
Hepcidin from the liver
What is the role of Hepcidin?
Prevents iron transport through ferroportin
Why does the liver want to diminish iron concentrations?
Infectious organisms need iron to grow; this is a strategy to combat infection
Outline the process of transferrin-bound iron uptake into cells.
1) Transferrin-bound iron binds transferrin receptor
2) Clathrin mediated endocytosis into endosome
3) ATPase acidifies the endosome
4) Change in transferrin conformation to release iron as Fe+++
5) Fe+++ is reduced to Fe++
6) DMT-1 transports Fe++ into the cytoplasm
Transferrin receptor is recycled back to the surface of the cell.
Once in the cytoplasm, how is iron stored?
As ferretin
What are the three anatomical locations with the highest concentrations of ferretin-bound iron?
1) Liver
2) Spleen
3) Bone marrow
When RBCs are destroyed in splenic macrophages, what happens to the iron? What happens to that iron when it is needed?
- Stored as ferretin in splenic macrophages
- On demand, iron is transported via ferroportin into the circulation
What organ produces hepcidin?
Liver
What is the function of hepcidin?
1) Blocks ferroportin in ENTEROCYTES
2) Blocks ferroportin in SPLENIC MACROPHAGES
At what level is ferretin regulated?
Post-transcriptional level via the “Iron Response Element” in the 5’ UTR of the mRNA
Describe how ferretin mRNA responds to free iron in the blood.
- Ferretin mRNA contains the IRE bound to Iron Regulatory Proteins (IRPs)
- Bound IRPs BLOCK translation
- Free iron binds IRPs, allowing for the translation of ferretin mRNA
What is alpha-ALA synthase?
Enzyme that produces heme
What is the effect of free iron on alpha-ALA synthase?
- Free iron increases alpha-ALA synthase
- Thus, free iron increases heme synthesis
What is the effect of free iron on the transferrin receptor?
Free iron binds IRPs, which STABILIZES mRNA to PREVENT translation
Thus, free iron DECREASES the synthesis of transferrin receptors
What is the clinical utility of a serum iron concentration?
Determining iron overload or iron poisoning
What is the “Total Iron Binding Capacity?” What is normal?
A measure of transferrin saturation
~30% is normal
What does a TIBC below 15% indicate?
Iron deficiency
What is the clinical utility of serum ferretin concentrations?
Best measure of body iron stores
What is red cell protoporphyrin?
The iron-free precursor of heme
What is an elevated red cell protoprophyrin an indication of?
Iron deficiency–not enough iron to complete heme synthesis
What are the five most common causes of iron deficiency anemia?
1) Blood loss
2) Chronic disease (inflammatory marks induce hepcidin)
3) Poor dietary intake
4) Intestinal parasite
5) Malabsorptive syndrome
What are the three stages of iron deficiency anemia?
1) Iron depletion
2) Deficient erythropoesis w/ normal Hb concentration
3) Iron deficiency anemia i.e. Hb production is inadequate
What are the common causes of iron overload?
1) Chronic blood transfusions
2) Inappropriate parenteral nutrition
3) Ineffective hematopoiesis
4) Hereditary uptake disorder e.g. Hemochromatosis
What is Hemochromatosis?
- Mutation of HFE gene that codes for Hepcidin
- Increased iron release
Where does heme synthesis occur in the cell?
Mitochondria
What is the committed, regulated step of heme synthesis?
ALA synthase
Succinyl-CoA + glycine= aminolevulinc acid (ALA)
What happens to ALA after it is synthesized in the mitochondria?
1) Transport into the cytosol
2) 2x molecules of ALA are joined by prophobilinogen synthase to form PBG
What happens after PBG is formed in heme synthesis?
4x PBG are joined to make uroporphyrinogen by uroporphyrinogen synthase
What happens to Uroporphyrinogen in heme synthesis?
Modifications are made in the cytoplasm and mitochondria to make
- coprophyrinogen
- protoporphyrinogen
What is the final step of heme synthesis? Where does it occur?
Mitochondira
Ferrochetolase inserts Fe++ into heme
What activates ALA synthase?
Iron
What inhibits ALA synthase?
- Heme
- Fe+++ heme
- Hemin
What is X-Linked Sideroblastic anemia?
- X-linked disorder that causes bone marrow to produce ringed sideroblasts vs. healthy RBCs
- Unable to produce sufficient heme
What is the gene mutation associated with sideroblastic anemia?
- Mutant ALA synthase encoded by the ALAS2 gene on the X-Chromosome
Results in reticuloytes that are unable to produce sufficient heme and accumulate iron, forming “siderblasts.”
What are “porphyrias?”
Diseases of heme synthesis
What is the enzymatic defect in Acute Intermittent Porphyria (AIP)?
Porphobilinogen deaminase deficiency
What products of heme synthesis accumulate in AIP?
ALA
PBG
Note that these products give the urine a dark red color.
What are the symptoms of AIP?
- Confusion
- Abdominal pain
What is the deficiency in Porphyria Cutanea Tarda (PCT)?
Uroporphyrinogen decarboyxlase
What is the hallmark of PCT when examining the urine?
Under UV light, urine will be pink flourescent
What product of heme synthesis builds up in Prophyria Cutanea Tarda?
Prophyrins
What is the hallmark symptom of PCT?
Photosensitivity of the skin leading to blistering
Porphyrins do NOT absorb visible and UV light; rather, this energy is dissipated into the skin of forms damaging ROS.
How does lead inhibit heme synthesis?
Inhibits 3 key enzymes:
1) Prophobilinogen synthase
2) Ferrochetalase
