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  1. 1. describe structure of Hb? What does each globin contain?
    2. What causes sickle cell anemia?

    3. What are forms of Fe in biology? (3)

    4. Iron RDA? (mg/day)

    5. Sources?

    6. Where is dietary heme found? in what form? What is its bioavailability?

    7. What enhances non-heme iron absorption? (2) What inhibits it? (5)
    1. tetrameric - 2 a-globulins, 2 B-globulins, each with a covalently bound, Fe-containing heme group

    2. Mutation in B-globin (HBB) gene leading to Hb protein aggregation

    3. Heme-bound Fe2+, ferric Fe3+, ferrous Fe2+

    4. ~15-18, 27 for pregnatn

    5. Sources - meat, fish, legumes, vegetables, fruits.

    6. Meat as Fe-protoporpyrin IX. 33-50% (high)

    7. Iron uptake is encouraged by vitamin C ,meat. Inhibitd by phytates, oxalates,  phosphates, tannins, soy protein
  2. 1. Where does heme syn take place? (2)
    2. What is the rate-limiting step? What vit does it require? 
    3. How many O2 can hb carry? Mb?
    4. Low pressure favors binding of O2 to what? Where is Mb?
    • 1. Cytosol, mitochondria
    • 2. ALA synthase (vitamin B6) - Fe is added to protoporphyrinIX on His-residue for mature Heme
    • 3. 4, 1
    • 4. Low pressure favors Mb. Mb is in myocytes, tissues.
  3. Functions of iron? (6)

    What is iron important for synthesizing? (6)
    • 1. Binding site for gases (Hb/Mb)
    • 2. Regulates enzyme activity (DNA synthesis)
    • 3. Regulates genes via tx and post-tx mechanisms
    • 4. Niacin, NO, DNA, carnitine, procollagen, thyroid hormone synthesis
    • 5. Health Antioxidant, destruction of bacteria, viruses, microbes
    • 6. ATP, carb metabolism, AA metaboliism
  4. Describe iron uptake (5) and transport (2)

    1. What regulates ferroportin? (2)
    2. What is hephaestin responsible for? What else is it called/ What does it have homoogy with?

    3. What must happen to Fe2+ before it can leave the cell? Why?

    4. What happens when you administer Cu to iron?

    5. How do sensing iron-regulatory proteins modulate synthesis of TfR, ferritin, and DMT1?
    • 1. Fe3+, Fe2+, Heme-Fe3+ is freed by HCl, proteases, etc from bound-nonheme iron and Hb/Mb
    • 2. Heme Fe3+ enters enterocyte via hcp1 --> heme oxygenase: Fe2+ + protoporphryin 

    Fe3+ is reduced into Fe2+ and all Fe2+ is absorbed by DMT1

    3. Fe2+ is bound to cytosolic protein then-->  functional use in cell or stored as ferritin

    5. Fe2+ is reoxidized to Fe3+ via hephaestin 

    6. Fe3+ is exported out of cell via ferroportin

    7. Fe3+ is loaded on to apotransferrin --> transferrin-Fe3+

    2. Upregulated by amount of available iron, downregulated by interaction with hepcidin

    3. Must be reoxidized to Fe3+ so it can bind to transferrin for transport

    4. Link between Fe-def and Cu-def, because admin of Cu helps export Fe out of tissues into circulation (hephaestin has homology with ceruloplasmin)

    5. IRP1 and IRP2 are cytosolic RNA binding proteins that bind to IREs on mRNA of ferritin, TfR, DMT1. Binding of IRPs at 5' end of transcripts decreases rate of synthesis, while binding at 3' end prolongs halflife of mRNA --> increased synthesis. 

    In iron overload, decreased TfR/DMT and increased ferritin (for adequate storage) and vice versa!
  5. 1. How is Fe stored? Where are these proteins found - tissue, cell? 
    2. What happens when ferritin accumulates? (4)
    3. What type of ferritin is present in mit? 
    4. What is missing link in iron absorption? What is the enzyme responsible for it? What upregulates this enzyme? 
    5. When is Fe2+ generated? When is Fe3+ generateD?
    1. Ferritin - ubiquitously, cytosol

    2. (1) Aggregates (2) proteolyzed by lysosomal enzymes (3) convertedto fe-rich, poorly characterized hemosiderin (4) iron is released slowly

    3. M-ferritin (expression is correlatd with tissues with lots of mit, not lots of iron)

    4. Why Fe3+ must be reduced to Fe2+ by ferrireductase - IRON DEFICIENCY

    5. Fe2+ is soluble at neutral pH but reactive with oxygen, it is generated in microenvironments for the purpose of crossing membranes. Fe3+ requires transferrin - not soluble at neutral pH
  6. 1. Master regulator of Fe?
    2. ^where is it syntheiszed?
    3. What type of intrinsic activity does it have?
    4. What does it result in? from where?
    5. What leads to increases in hepcidin? (3)
    6. What leads to decreases in hepcidin ? (3)
    • 1. Hepcidin
    • 2. Hepatocytes 
    • 3. Intrinsic antimicrobial activity
    • 4. REDUCES efflux of iron from cells (intestine, macrophages) to plasma by destroying ferroportin
    • 5. Iron overload, late hematochromatosis, inflammation
    • 6. Iron depletion, anemia, hypoxia.
  7. How is hepcidin regulated? (2)

    1. HFE-TfR2
    2. Inflammation (3)
    By hemojuvelin produced from HFE gene (inhibits hepcidin)

    1. Iron sensors - (1) HFE protein interacts with TfR1, but HFEprotein dissociates with Fe-Tf binds to TfR1. TfR2 competes with TfR1 for binding to HFE. HFE-TfR2 may regulate hepcidin expression by promoting HJV/BMP signaling --> activating synthesis and secretion of hepcidin --> hepcidin reduces circulating Fe

    2. IL-6 (via STAT3-dep tx mechs) and macrophages induce/express hepcidin in response to inflammation and microbial stmiulation. Inflammatory stimuli also act through TNF-a to suppress HJV mRNA --> releasing inhibition on hepcidin synthesis
  8. 1. Is hepcidin high or low in anemia (including sickle cell?) Why?

    2. when is it elevated?

    3. Describe uptake of circulating iron (4)

    4. What happens when hepcidin is overexpressed?
    1. Low to allow fe uptake and recycling from macrophages. Problem in sickle cell anemia

    2 In resopnse to sickness, chronic infection/inflammation, cancer

    • 3. (1) 2 TfR-Fe binds to 1 TfR and becomes endocytosed
    • (2) Iron is off-loaded in acidified endosomes while apotransferrin-TfR complex is recycled back and ApoTf is released back into circulation
    • (3) Endosomal compartment releases Fe3+ and Steap3 reduces it to Fe2+
    • (4) Fe2+ leaves endosome via DMT1
    • (5) Fe2+ can then be incorporated into proteins or stored in ferritin

    4. Pale, anemic animals with no hair. 4x total less body iron and anemia
  9. 1. What is primary vs. secondary hemochromatosis?
    2. Where does iron accumulate (3) and what does it do to the organs
    3. What happens to transferrin saturation and serum ferritin? 
    4. Therapy for primary vs. secondary?
    1. Primary - excessive iron absorption from gut. Secondary = transfusion-dependent anemias (leukemia)

    2. Iron accumulates in liver, heart, pancreas --> excess Fe3+ damages these organs by free radical production

    3. Both Tf saturation and serum ferritin increase

    4. Primary - phlebotomy, decrease of iron in circulation leads to mobilization from stors. Secondary - iron chelators
  10. 1. What is most prevalent nutr def?
    2. Who is at risk? (3) bc of why?
    3. What is hallmark of RBCs in iron def?
    4. What happens to ferritin, Tf, and O2 delivery?
    5. What are stages of iron depletion (5)
    6. Symptoms?
    • 1. Iron
    • 2. Infants, school-age children, pregnant women (increases in Fe reqs)
    • 3. Hypochromic microcytic RBCs (small, decreased Hb content)

    4. Decrease

    5. Normal --> early negative Fe balance --> iron depletion --> iron-def erythropoesis - syn of RBCs --> Iron deficient anemia (microcytic anemia)

    6. Irritability, poor attention span, lack of interest, poor work performance, behavioral disturbances, defective structure/function of epithelial tissues, increased infection, pica
  11. 1. How does anemia relate to iron deficiency? can you have anemia w/o iron def?

    2. what is anemia? What does it result in?

    3. Common causes? (5)

    4. What is a distinguishing feature of anemia? (2)

    5. Symptoms? Short-term - affects so much

    6. Long-term
    1Anemia is a trait of iron def, but you can have anemia without iron deficiency

    2. Anemia is condition in which [Hb] in blood is below a defined level, resulting in reduced O2-carrying capacity of RBCs

    3. Iron-def, hookwarm, vitamin A, B9/B12 def (not as common), malaria infection

    4. Distinguished by reticulocyte count (increased destruction, decreased production)

    5. Fainting, chest pain, angina, heart attack, weakness

    6. Long-term consequences, poor immunity, fatigue, poor physical growth, increased risk of complications during pregnancy, impaired neurocognitive function in children
  12. 1. What does pregnancy anemia cause in babies? 4

    2. How is anemia diagnosed? (5)
    1. preterm, FGR, preterm and FGR --> perinatal death

    2. (1) Low Hb/hematocrit (below ~11 g/DL and below ~33-39% hematocrit (2) Hypochromia, microcytotic RBCs (3) low serum iron and ferritin (4) Total plasma iron-binding capacity - elevated Tf - high (5) field test - hemocue
  13. 1. What are the main biological roles of Zn, Cu, Mn 4

    2. Determinants of biolgoical roles (4) Who exhibits most of these features? which are better for redox rxns?

    3. general functions of zinc? (5)
    1. Signaling, structural, catalytic, regulatory

    2. (1) ion charge - stability and reactivity (2) size of atom - limits fitting in active site (3) flexible coordination geometry (4) natural abundance/location within cell. Zn. Cu & Mn

    • 3. 
    • (1) catalytic role in over 300 enzymes
    • (2) Structural - transcription factor in zinc motifs
    • (3) Regulatory - regulation of gene expression via MRE1, cell signaling pathways
    • (4) regulation of growth (via IGF-1 secretions)
    • (5) Regulation of immunity - Zn def reduces total lymph B and T --> Cu def results in neutropenia and lower numbers of lymph T
  14. 1. Sources of Zn?
    2. RDA? 
    3. Assessment of Zn status? (4)
    4. UL?
    • 1. Meat (beef/lamb)
    • 2. ~11, UL = 40
    • 3. Serum levels (but are influenced by daily factors), metallothianein, urinary excretion - good for detecting mod/severe, hair zinc content
  15. Describe Zn intesitnal intake (8)

    What are the main transporters of Zn? (3)

    Where is most of the Zn taken? Where is Zn initially stored?

    How is Zn taken up by cells? 

    How is zinc mobilized?
    • 1. Bound zinc is broken down by HCl, proteases, nucleases into free Zn2+
    • 2. Most Zn is absorbed by ZIP4 across brush border membrane
    • 3. DCT-1 and amino acids may play minor role in Zn absorption across brush border membrane
    • 4. Some Zn2+ may be directed into feces if bound to inhibitors or absorption may be enhanced by organic acids, low pH, or chelators
    • 5. With high Zn intakes, Zn may be absorbed between cells via paracellular diffusion
    • 6. Within cells, Zn may be used functionally or stored in vesicles in the trans-Golgi network or as part of metallothionein (during high Zn status).
    • 7. Zn may be transported across BL membrane by ZnT1 into blood
    • 8. Zn can bind to lots of diff proteins for transport in blood. (alumin, transferrin, etc)

    (1) Albumin (60%), a-2macroglobulin (40%), Amino aids (3%)

    Initially stored and taken to liver

    Via ZIPs and ZnTs on cellular membrane, within golgi apparatus, etc. 

    Via transcription dep/indep methods. First will exhaust stores then create influx.
  16. 1. Are there significant storage pools for Zn, Cu, Mn? Where are they found? Mostly where?

    2. What is metallothionein (MT). Where is it concentrated ? (4)

    3. What does MT control? What does it respond to? (2) What is it produced in response to? (4)

    4. How does MT regulate Zn2+ levels? 

    5. How does Zn regulate MT? What is it stronger than? What might this explain?

    6. How is most of Zn excreted? Where else? (3)

    7. What does Zn def lead to?
    1. NO. Everywhere. Mostly muscle, bones, liver, etc. 

    2. Cytosolic, metal-binding protein that is concentrated in liver, kidney, pancreas, intestine

    3. Controls free Zn2+. Responds to diet and hormones. 

    Produced in response to high Zn2+, Cu2+, Cd, and Hg

    4. Excess Zn: MT blocks Zn movement across enterocyte. Block metal is excreted with dying enterocyte. 

    5. In cell, Zn may aggregate into Zn-protein-MTF which binds to MRE promoting increase in mRNA of thionein --> increased thionein and zinc leads to increase storage MT. 


    why Zn blocks Cu absorption

    6. 80% feces. Also urine, hair, sweat

    7. Growth retardation, impaired immune function, delayed sexual maturation, alopecia, poor wound healing, loss of sense of taste
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