1. What is primary function of Fe? 4 other functions?
2. How efficiently is it conserved/reused?
3. What's a bad thing about iron? What does this mean?
1. O2 carrier - immune function, cognitive development, temp regulation, energy metabolism
- 2. ~90% is conserved and recycled
- 3. It's highly toxic - must be highly regulated
1. What are the two forms of iron and how are they found in foods? (2,1)
2. What are sources of each form?
3. Which one is strongly influenced by dietary components? Which dietary components? (3)
4. What enhances Fe absorption? How?
- 1. Heme (porphyrin ring complex) and nonheme (free or in complex form)
- 2. Heme - meat, dairy; nonheme - plants (spinach)
- 3. Nonheme (heme isn't affected by other dietary components) - polyphenols, soy, and phytatic acids.
- 4. Vitamin C - reduces Fe3+(ferric) --> Fe2+(ferrous) and Fe2+ is more absorbable
1. What is the major class of proteins involved with irons? Name 3 examples.
2.What is iron's role in photosynthesis? What form does what? Who does this help?
3. Draw iron dependent activities in cells (6 boxes - 2 boxes have two headings, one box has one heading and two things under it) - two are under same category
- 1. Hemoproteins - Hb, Mb, cytochromes
- 2. Fenton chemistry - Fe-S cluster converts light energy to chemical energy that fuels non-photosynthetic organisms.
1. Which position around iron is occupied by O2?
2. In oxy or deoxy form is heme domed? What is the other structural shape?
3. Where is iron absorbed? (2)
4. Describe absorption of heme iron (4)
5. Describe absorption of non-heme iron (6)
- 1. 6th
- 2. Deoxy - Domed; oxy - planar
- 3. Duodenum and jejunum
- 4. Nonheme iron:
- 1. Metal porphyrin ring removed from globin
- 2. Heme-carrier protein 1 (HCP1) transports heme into enterocyte
- 3. In enterocyte, heme may be split further from Fe2+ and bilirubin by heme oxygenase and biliverdin reductase
- 4. Free Fe2+ exits portal circulation via ferroportin-mediated basolateral transport with non-heme iron.
- 1. Low pH and digestive enzymes release nonheme iron from foods
- 2. Found in diet as Fe2+ or Fe3+ - in stomach, rapidly oxidized to Fe3+
- 3. Dcytb (reductase in enterocyte + Vitamin C as cofactor): Fe3+ --> Fe2+ for better absorption
- 4. DMT1 (divalent metal transporter1) transports Fe2+ into enterocyte
- 5. Ferroportin (MTP1) Fe-regulated protein transfers Fe2+ from enterocyte to circulation
- 6. Hephaestin - facilitates iron exit from enterocyte by oxidizing iron released through ferroportin
1. Where is ferroportin found? (7)
2. When Fe2+ is transported out of enterocyte into circulation, what immediately acts on it? (2) To do what?
3. What is the main transporter of iron? What form of iron and how many?
- 1. Liver, spleen, kidney, heart, placenta, duodenum ...pretty much everywhere
- 2. hephaestin or ceruloplasmin - to oxidize to Fe3+
- 3. Transferrin - Fe3+ (2)
1. Name receptors for iron uptake - where are they found? affinity for transferrin-Fe3+ complex?
2. What is saturation level of circulating transferrin? Why?
3. What is Fe-free form of transferrin called?
- 1. TfR1 - all dividing cells, but especially RBCs - higher affinity; TfR2 - primariy in liver, binds at much lower affinity than TfR1.
- 2. 20-30% to act as sink to avoid danger of free/unbound iron.
- 3. Apotransferrin
1. Describe mechanism of iron uptake? (5)
2. What is storage protein for iron? Is it highly conserved in genomes? What happens if you delete it from embryonic mice?
- 1. Transferrin-Fe3+ complex binds to receptor
- 2. TfR-Fe3+-Receptor complex is internalized via receptor-mediated endocytosis by clathrin-coated pits
- 3. Complex is acidified to induce conformational change releasing iron (Fe3+)
- 4. STEAP: Fe3+--> Fe2+
- 5. Transferrin is recycled by endosomes
2. Ferritin; yes; they die.
1. What is controlled in iron homeostasis?
2. What is the main regulating factor?
3. Very generally, what does high iron cause in these controlled factors? (2) Low iron? (2)
- 1. TfR gene expression and ferritin gene expression
- 2. Amount of iron
- 3. High iron causes decrease in TfR exp and increase in ferritin; opposite.
How does iron control ferritin levels?
1. What are the actors? What do they bind to?
2. What happens in high iron situations?
3. What happens in low iron situations?
4. What does acontinase do?
- 1. Two forms of iron-response proteins (IRP1 and IRP2) bind to 5'IRE (iron response element) on ferritin mRNA?
- 2. High iron: (1) IRP-1 gains acontinase activity (Fe-S cluster)--> no IRP activity. (2) IRP2 is degraded by proteasomes. No inhibition from IRP allows gene transcription of ferritin.
- 3.IRP1 and IRP2 are formed and bind to mRNA inhibiting gene transcription.
- 4. Acontinase: citrate --> isocitrate to form IRP1 and inhibit ferritin translation
Iron and transferrin receptors
1. What does transferrin receptor contain?
2. What do these regions do?
3. What is IRPs role? How is transcription affected?
4. Write equation for low iron and high iron.
- 1. IREs in 3'noncoding loop of mRNA
- 2. Destabilize mRNA and promote its degradation
- 3. IRP binds to mRNA, stabilizes IREs, allowing for increased transcription.
- 4. Low iron + IRP1 binds 3'IRE = increased TfRe.
High iron = no IRPs = no binding to mRNA = no stabilization = less transcription.
1. Basically, what do IRPs do for transferrin and ferritin and when are IRPs expressed?
2. What is hepcidin?
- 1. IRPs are expressed during low iron - decreased transcription of ferritin mRNA by binding and increased transcription of transferritin mRNA by binding mRNA and stabilizing it.
- 2. Hepatic peptide hormone
1. What does hepcidin act on? (1) How? (3)
2. What is the result of hepcidin's actions?
3. What are three factors that hepcidin regulated by? (3)
4. What happens if hepcidin or ferroportin are dysregulated?
5. How does high iron affect hepcidin?
- 1. Hepcidin acts on ferroportin: binds to it, degrades ferroportin protein causing loss of function.
- 2. Blocks iron release from enterocytes into circulation.
- 3. Iron levels, anemia and hypoxia
- 4. Range of iron disorders
- 5. High iron increases hepcidin mRNA expression!
1. What is HAMP gene responsible for?
2. What is HAMP gene regulated by? (5)
3. What happens to iron that is blocked? in which 3 locations?
4. What is master regulator of iron?
- 1. Hepcidin release
- 2. Iron, hemojuvelin, TfR2, infection, HFE
- 3. Iron is trapped in short-lived enterocytes which shed from gut in 1-2 days, taking iron with it (also traps iron in macrophages and hepatocytes by same mechanism)
- 4. Hepcidin
1. What does RBCs long lifespan indicate for deficiency?
2. Which 2 groups need the most iron?
3. What do RBCs look like in iron-def anemia? 3
- 1. Tissues/organelles may experience functional lack of iron before significant change in hematological parameters
- 2. Pregnant women and growing peope.
- 3. Microcytic - small, pale RBCs.
1. What must be measured in iron deficiency? Functional iron (4), tissue iron supply (3), iron stores (2).
2. What is the distinctive method?
1. Functional iron - [Hb], RBC indices (MCV, MCH), RBC Zn protoporphyrim, serum transferrin receptor)
Tissue iron supply- serum iron, serum binding capacity, saturation of transferrin
Iron stores - serum ferritin and tissue biopsy (liver or bone marrow)
1. Most dominant genetic problem causing hemochromatosis?
2. Describe crypt cell hypothesis (3)
3. Describe hepcidin hypothesis (1. normal conditions - 3; 2. mutant conditions -2)
- 1. Defect in HFE gene
- 2. Crypt cell hypothesis: (1) Transferrin saturation is detected by TfR1/HFE/B-2microglobulin. (2) If low, transferrin-mediated endocytosis is stimulated, increasing uptake of iron into crypt cells. (3) If there's a mutation in HFE, there will be decreased iron uptake into crypt cells.
Hepcidin hypothesis: Normally, diferric transferrin competes with HFE for binding to TfR1. Freed HFE binds to TfR2 leading to synthesis and secretion of hepcidin --> circulating hepcidin triggers ferroportin degradation.
In mutated HFE, can't activate hepcidin synthesis and secretion, so ferroportin is always on, increased iron influx into circulatino from duodenum, macrophages, etc.
1. Which is more likely - iron deficiency or iron overload?
2. Four symptoms of iron def?
3.5 symptoms of iron overload?
4. What is treatment for each? (def-2, overload - 2)
- 1. Iron def (>2 billion people have it worldwide and >9 million, whereas only 1 million US have iron overload)
- 2. Iron def - anemia, lowered work capacity, impaired mental function, impaired immune function
- 3. Iron overload - fatigue, liver diseases, neuropathy, cardiomyopathy, diabetes, etc.
What are other ways of correcting iron deficiency specifically? (food-based methods, iron supp, and other)
1. Food based approaches - improve availability of iron rich foods, change feeding patterns to enhance bioavailability of iron, food fortication/biofortification
- 2. Iron supplementation - preventative iron supplementation especially for at-risk groups
- 3. Other reasons - control intestinal parasites
What is most common trace element def in world? What % of world's population has this?
2. What does malnutrition of iron lead to in people?
- 1. Iron, 20-50%
- 2. immune dysfunction