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43 Cards in this Set
- Front
- Back
where is most iron in our body?
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• majority bound to heme prosthetic group (porphyrin ring)
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percent iron in heme of hemoglobin
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65% (most)
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percent iron in heme of myoglobin
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10%
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percent heme on other heme containing enzymes
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1-5%
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other heme containing enzymes
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• cytochome P450s
• cytochromes that are part of electron transport chain |
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non-heme iron
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• bound to non-heme enzymes that have iron sulfur clusters
• transferrin (carries iron in blood) • ferritin (stores iron in cells) |
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how do different side chains of porphyrin ring affect iron?
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• microenvironment changes electronic properties of Fe (oxidation-reduction potential of iron varies from protein to protein)
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two forms of iron
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Fe3+ + e- <-> Fe2+
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oxidized form of iron
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• Fe3+
• lose electrons=oxidized (LEO GER) |
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reduced form of iron
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• Fe2+
• gain electrons=reduced |
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result of undesired (non-enzymatic) redox reactions catalyzed by irons
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• reactive oxygen species form
• damage and toxicity result |
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Fenton Reaction
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• only Fe2+ form will do this, so want to store in Fe3+ form
• Fe2+ + H2O -->Fe3+ + OH- + OH• • OH• is a hydroxyl radical--highly reactiveextract hydrogen from nearby macromoleculeDNA mutation, lipid peroxidation (which leads to more free radicals being produced) |
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5 tests to measure serum iron levels
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• serum iron
• total iron binding capacity • percent transferrin saturation • serum ferritin • hemoglobin and hemotocrit (no best…) |
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serum iron
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total circulating iron in serum
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total iron binding capacity
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TIBC=total amount of tranferrin
percent transferrin saturation: TSAT, how much total transferrin is bound bu iron (serum iron/total iron binding capacity), normally 30% |
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serum ferritin
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total amount iron stored in body
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hemoglobin and hemotocrit
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will tell if anemic, but the last parameter to change, so do not carch anemia as early as with other tests
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transferrin
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• carrier protein for Fe3+ state iron in plasma
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uptake of transferrin bound to Fe3+
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• transferrin receptor (TfR) on cells
• endocytosis to endosome • Fe3+ released in endosomes • TfR recycled to PM • TfR synthesis regulated by cellular iron levels |
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ferritin
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• multi-subunit
• can hold 4500 Fe3+ • every cell type in body (since all need iron…) • ferroxidase activity=convert Fe2+ to Fe3+ • synthesis regulated by iron levels |
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where is iron stored in the body?
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• bound to ferritin in cells
• liver stores 60% of body’s iron • also stored in reticuloendothelial cells in the spleen and bone marrow (make hemoglobin) |
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cellular uptake and storage of iron
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• Fe3+ bound to tranferrrin binds TfR on cell surface
• endocytosis to endosome • in endosome, Fe3+ dissociates from transferrin • in endosome, ferrinreductase converts Fe3+ to Fe2+ • DMT-1 in membrane of endosome transport Fe2+ (only reduced form) out of endosome • Fe2+ binds ferrintin in cytosol • ferroxidase activity of ferritin converts Fe2+ to Fe3+ |
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where is iron homeostasis regulated in body
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• intestinal absorption
• we really have no mechanism for losing iron, just uptake • iron only really lost through shedding of intestinal and skin cells and blood loss--not something that is easily regulated • also can regulated mobilization of Fe from body iron stores (liver, macrophages) |
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free iron absorption
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• stomach acid and digestive proteases free non-heme from proteins
• ferrireductases on luminal surface intestinal enterocytes convert Fe3+ to Fe2+ (requires vitamin C (electron donor)) • DMT1 transport Fe2+ across luminal plasma membrane of intestinal mucosal cell • in cell, ferritin binds, converts Fe2+ to Fe3+ and temporarily stores iron • ferrireductase converts Fe3+ to Fe2+ for transport across membrane • ferroportin (basolateral membrane) transport Fe2+ across basolateral membrane--REGULATED STEP!! • ferroxidase converts Fe2+ to Fe3+ during transport (contains Copper, copper deficiency can lead to iron deficiency) • Fe3+ binds transferrin in the blood (2 per transferrin) • transported to tissues |
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what form does iron need to be in to be transported across membranes?
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• Fe2+ form (less stable form)
• convered from Fe3+ to this form by ferrinreductase |
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how is Fe2+ converted back to Fe3+
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• ferroxidase activity of ferritin in cells
• or ferroxidase after it is exported from cell by ferroportin |
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protein that transports Fe2+ across apical cell membrane into enterocyte
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DMT1
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protein that transports Fe2+ across basolateral membrane of enterocyte so can enter capillary
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ferroportin
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protein that reduces Fe3+ to Fe2+ outside of cell in intestinal lumen so can be transported into enterocyte
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ferrireductase (requires Vitamin C)
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How can Copper deficiency also result in Fe deficiency?
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• Cu is necessary for ferroxidase activity, which converts Fe2+ back to Fe3+ after crosses basolateral membrane of enterocyte--without this converstion, Fe2+ would remain and this form does NOT bind to transferrin, which is the carrier protein to move Fe to cells
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how do we regulate iron absorption?
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• hepcidin!
• high levels iron reduce DMT1 levels |
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how does hepcidin work?
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• polypeptide hormone
• released from liver (liver senses how much Fe is bound to transferrin) • decreases Fe internalized in response to high iron levels • high iron levels-->liver -->hepcidin secretion-->binds ferroportin-->ferroportin internalized-->reduces transport of Fe from intestine to blood |
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main protein responsible for regulating intracellular iron levels and its unique features
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• Iron Regulatory Protein (IRP)
• non-heme iron protein • under normal Fe conditions, acts as a metabolic enzyme in TCA • under low iron conditions, will lose Fe from its Fe-S clusters and lose its enzymatic activity to become and RNA binding protein • regulates ferritin mRNA and transferrin receptor (TfR) mRNA POST-TRANSCRIPTIONALLY |
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iron regulatory protein effect in low iron conditions
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• reduces ferritin translation-->decreased Fe storage in cells-->iron is mobilized/ freeded up and more Fe is available
• increases TfR mRNA translation-->more transporters means more Fe can be brought into blood circulation from the intestine |
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mechanism of action or IRP on ferritin at low iron conditions
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• IRP loses iron from its FE-S cluster-->enzymatically inactive--> becomes a RNA binding protein-->binds Irons Response Element (IRE) in 5’ UTR ferritin mRNA-->blocks ribosomes from translating ferritin-->decreased ferritin-->decreased Fe storage-->more Fe available
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mechanism of action or IRP on TfR at low iron conditions
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• IRP loses iron from Fe-S cluster-->becomes RNA binding protein-->binds IREs in 3’ UTR of TfR mRNA-->stabilizes from degradation-->increased TfR mRNA-->increased TfR-->increase Fe import-->increase Fe available
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iron regulatory protein effect in high iron conditions
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• ferritin is translated, so Fe can be stored attached to ferritin in cells, decreases free iron available
• TfR is degraded, so less transporters means less Fe imported from intestine, decreases Fe levels |
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mechanism of action or IRP on ferritin at high iron conditions
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• IRP does not lose iron from Fe-S cluster-->NO binding to 5’UTR of ferritin mRNA-->normal ferritin translation-->increase ferritin levels-->Fe storage-->decreases Fe available
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mechanism of action or IRP on TfR at high iron conditions
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• IRP does not lose iron from Fe-S cluster-->NO binding to 3’ UTR of TfR-->TfR mRNA rapidly degraded-->decrease TfR-->decreased Fe import-->decreased Fe available
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mutation in hepcidin
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• mutation that causes reduced levels of hepcidin-->hemochromatosis (iron overload due to enhanced iron absorption)
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anemia
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too little iron, insufficient Hb to carry O2 to tissues, most common cause are parasitic infections that cause intestinal blood loss at rate faster than new Hb can be made
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hemochromatosis
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• genetic disorder, iron accumulates, chronic toxicity
• treat by phlebotomy • most common genetic disorder in the world |
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most common mutation associated with hemochromatosis
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• most common mutation=HFE gene that regulates hepcidin induction in response to high iron-->reduced hepcidin levels=enhanced iron absorption
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