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38 Cards in this Set

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What levels of Iron are required? How much is stored inside?
Trace element: ~15mg/day (more if menstruating woman)
2-5 g inside of us
Where is iron found in the body?
60-70% in hemoglobin
10% myoglobin
<1% cytochromes, metalloenzymes
Variable amount in ferritin/hemosiderin
What % of iron absorbed?
How is the rate improved? inhibited?
HEME: 25-35%
Non-heme: 1-3%
Improved: ascorbic acid, "meat factor"
Inhibited: Chelators, tannins
How is iron homeostasis maintained?
Through absorption (OUT of the intestinal cell).
Describe the mechanism of Iron absorption INTO cell
Into cell:
HCP1 transports HEME in
Dcytb reduces Fe3+ to Fe2+
DMT1 transports Fe2+ in

Only Fe2+/Heme absorbed
Ok, so heme and Fe2+ inside cell - how is it contained?
Heme broken down by heme oxigenase;
Fe2+ in "pool"
Some binds to ferritin (storage form)
Describe the mechanism of Iron absorption OUT of the cell
Ferroportin transports iron out, shuttle iron to hephaestin oxidizes Fe2+ to Fe3+
Fe3+ combines with transferrin (two Fe's per transferrin)
What does hephaestin do? What element does it contain?
Contains copper
What cells contain ferroportin?
Cells that need to excrete iron:
hepatocytes, enterocytes, macrophages
How is iron absorption regulated?
By varying the number of ferroportin transporters on the basal lateral side of the cell: Increases/decreased amount of hepsidin. Hepsidin binds to ferroportin and causes internalization/break down.
How are hepcidin levels regulated?
Hepcidin is excreted by the liver in response to status of TfR (transferrin receptor). Occupied = high iron = hepcidin released.
How is iron taken up by cells?
Number of TfR on cells regulated based on intracellular iron levels. Low = more TfRs.

TfR has high affinity for diferric transferrin.
What cells have high # of TfRs?
# of TfRs is indicative of that cell's overall iron requirement

- liver, placenta, erythocyte precursor cells
What is TfR?
Transferrin Receptor

It's a transmembrane glycoprotein
Once iron is abssorped into a cell, what are its fates?
Erythroblast precursors: hemoglobin; muscle: myoglobin; Fe-dependent enzymes; Ferritin
How many iron atoms can ferritn store? What is the storage form?
A SHITLOAD: like 4500+
Stored in the center of the molecule as ferric oxyhydroxide
What spots appear when iron stores get too high? What forms these spots?
Hemosiderin deposits formed from ferriton by lysosome. Iron precipitates out.
Describe the mechanism of iron uptake
See notes.
Some hints - TfR on surface; transferrin binds; complex moves to clathrin-coated pit; endocytosis ensues; endosome internalized.
How is the iron removed from the endosome?
Proton pumps acidify the endosome internally; TfRs release iron; remaininer moves back to membrane surface and merges - TfR and apotransferrin reused.

Of course- iron fate depends on cell type.
What type of transferrin binds to TfR?
Diferric transferrin
What are the main sources of iron loss?
Women - menstruation, pregnancy
Others: donating blood;
Urinary, bile, skin
! Worldwide = hookworm
How many people WW are affected by hookworm? How does it affect children?
About 1/5; 1/4 of those people also have anemia.

In kids, can cause permanent problems with growth and cognitive, behavioral function.
How is intracellular iron regulated? (general)
By controlling:
1. Number of TfRs
2. Amount of ferritin
This is accomplised by regulation at the mRNA level for both, although mechanism are different
Descibe the difference (ie w mRNA) in how ferritin is regulated vs. TfR.
Ferritin levels are regulated by the rate of transcription of the mRNA.

TfRs are regulated by control over the the amount of mRNA present (which is controlled by the rate of degradation of the mRNA by nuclease enzymes).
How is the regulation accomplised?
Both have IRE (iron response element); IRP (iron response protein) binds in low iron levels "high affinity state". Not bound in high iron state since Fe-S binds to IRP "low affinity state".
Describe how IRP bound to IRE (in low iron status) affect mRNA of ferritin/TfR
When bound, it prevents mRNA of ferritin from being transcribed-- no ferritin made. When bound to TfR mRNA, it protects the mRNA from degradation.
What happends when iron levels are high?
Iron forms Fe-S complex and bind to IRP, changing it into "low affinity state". Unbound to IRE, ferritin can now me made and mRNA of TfR destabilized, broken down.
Why is ferritin mRNA stored at a constant level and not made when needed?
Because of iron's toxicity to cells!!
What are the biochemical roles of heme iron?
Heme: O2 transporter (hemo/myoglobin) and in cytochromes (heme-containing enzymes)
What are the biochemical roles of NONheme iron?
Fe-S proteins and Metalloflavoproteins - proteins involved w/TCA cycle (NADH dehydrogenase/succinic dehydrogenase)
Many other iron-dependent enzymes that need iron as a co-factor or activator
What are symptoms of iron deficiency?
Decreased work capacity, numbness/tingling, atrophy of tongue epithelium, Pica

~30% of ww pop!!!!!!
What are the three stages of iron deficiency development?
Iron depletion
Iron deficient erythropoiesis
Iron deficiency anemia
How is each stage assesed?
1. ferritin down, transferrin down, test to measure % transferrin saturated (typical 35%)
2. high levels of protoporphyrin (heme precursor); tests of endurance too
3. Hemoglobin can detect
To test for saturated level of transferrin, what is the number measured called?
UIBC
Unsaturated iron binding capacity (it goes up with low iron)
What are symptoms of hereditary hemochromatosis?
Eary signs: fatigue, heart palpatations.. hemosiderin deposits.

Late signs: liver enlargement, Diabetes, skin pigmentation. These are gen. irreversible!
What is the cause of HH?
It's caused by a genetic inborn error of metabolism. 80%+ have HFE gene mutation.

Homeostasis of iron not maintained. Large absorption due to decreased hepcidin secretion, and no down-regulation of iron absorption by ferroportin #s.

Due to HFE mutation, TfR's not "blocked" and so no cellular inhibition of absorption.
Who is affected by HH?
People of N European descent. 1:200-500. ~5% of US pop has this disorder.
How is HH treated?
Phlebotomy. Initially at levels of 1 pint/week!!!