Smp 43 Iron Metabolism

Front 1

where is most iron in our body?

Back 1

• majority bound to heme prosthetic group (porphyrin ring)

Front 2

percent iron in heme of hemoglobin

Back 2

65% (most)

Front 3

percent iron in heme of myoglobin

Back 3

10%

Front 4

percent heme on other heme containing enzymes

Back 4

1-5%

Front 5

other heme containing enzymes

Back 5

• cytochome P450s
• cytochromes that are part of electron transport chain

Front 6

non-heme iron

Back 6

• bound to non-heme enzymes that have iron sulfur clusters
• transferrin (carries iron in blood)
• ferritin (stores iron in cells)

Front 7

how do different side chains of porphyrin ring affect iron?

Back 7

• microenvironment changes electronic properties of Fe (oxidation-reduction potential of iron varies from protein to protein)

Front 8

two forms of iron

Back 8

Fe3+ + e- <-> Fe2+

Front 9

oxidized form of iron

Back 9

• Fe3+
• lose electrons=oxidized (LEO GER)

Front 10

reduced form of iron

Back 10

• Fe2+
• gain electrons=reduced

Front 11

result of undesired (non-enzymatic) redox reactions catalyzed by irons

Back 11

• reactive oxygen species form
• damage and toxicity result

Front 12

Fenton Reaction

Back 12

• only Fe2+ form will do this, so want to store in Fe3+ form
• Fe2+ + H2O -->Fe3+ + OH- + OH•
• OH• is a hydroxyl radical--highly reactiveextract hydrogen from nearby macromoleculeDNA mutation, lipid peroxidation (which leads to more free radicals being produced)

Front 13

5 tests to measure serum iron levels

Back 13

• serum iron
• total iron binding capacity
• percent transferrin saturation
• serum ferritin
• hemoglobin and hemotocrit (no best…)

Front 14

serum iron

Back 14

total circulating iron in serum

Front 15

total iron binding capacity

Back 15

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%

Front 16

serum ferritin

Back 16

total amount iron stored in body

Front 17

hemoglobin and hemotocrit

Back 17

will tell if anemic, but the last parameter to change, so do not carch anemia as early as with other tests

Front 18

transferrin

Back 18

• carrier protein for Fe3+ state iron in plasma

Front 19

uptake of transferrin bound to Fe3+

Back 19

• transferrin receptor (TfR) on cells
• endocytosis to endosome
• Fe3+ released in endosomes
• TfR recycled to PM
• TfR synthesis regulated by cellular iron levels

Front 20

ferritin

Back 20

• 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

Front 21

where is iron stored in the body?

Back 21

• 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)

Front 22

cellular uptake and storage of iron

Back 22

• 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+

Front 23

where is iron homeostasis regulated in body

Back 23

• 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)

Front 24

free iron absorption

Back 24

• 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

Front 25

what form does iron need to be in to be transported across membranes?

Back 25

• Fe2+ form (less stable form)
• convered from Fe3+ to this form by ferrinreductase

Front 26

how is Fe2+ converted back to Fe3+

Back 26

• ferroxidase activity of ferritin in cells
• or ferroxidase after it is exported from cell by ferroportin

Front 27

protein that transports Fe2+ across apical cell membrane into enterocyte

Back 27

DMT1

Front 28

protein that transports Fe2+ across basolateral membrane of enterocyte so can enter capillary

Back 28

ferroportin

Front 29

protein that reduces Fe3+ to Fe2+ outside of cell in intestinal lumen so can be transported into enterocyte

Back 29

ferrireductase (requires Vitamin C)

Front 30

How can Copper deficiency also result in Fe deficiency?

Back 30

• 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

Front 31

how do we regulate iron absorption?

Back 31

• hepcidin!
• high levels iron reduce DMT1 levels

Front 32

how does hepcidin work?

Back 32

• 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

Front 33

main protein responsible for regulating intracellular iron levels and its unique features

Back 33

• 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

Front 34

iron regulatory protein effect in low iron conditions

Back 34

• 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

Front 35

mechanism of action or IRP on ferritin at low iron conditions

Back 35

• 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

Front 36

mechanism of action or IRP on TfR at low iron conditions

Back 36

• 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

Front 37

iron regulatory protein effect in high iron conditions

Back 37

• 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

Front 38

mechanism of action or IRP on ferritin at high iron conditions

Back 38

• 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

Front 39

mechanism of action or IRP on TfR at high iron conditions

Back 39

• 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

Front 40

mutation in hepcidin

Back 40

• mutation that causes reduced levels of hepcidin-->hemochromatosis (iron overload due to enhanced iron absorption)

Front 41

anemia

Back 41

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

Front 42

hemochromatosis

Back 42

• genetic disorder, iron accumulates, chronic toxicity
• treat by phlebotomy
• most common genetic disorder in the world

Front 43

most common mutation associated with hemochromatosis

Back 43

• most common mutation=HFE gene that regulates hepcidin induction in response to high iron-->reduced hepcidin levels=enhanced iron absorption