B14 Iron metabolism Flashcards
Roles of iron in the body (6)
- redox functions due to ability to exchange between ferrous and ferric state
- cofactor for heme (hence O2 binding)
-ETC roles: Fe-S centers, TAC regulation
-collagen synthesis
-neurotransmitter synthesis
-eicosanoid synthesis
what human proteins is iron contained in
CAN BE HEME OR NON HEME:
HEME: Mb, Hb, HO1/2, catalase, NOS, CytP450
NONHEME: transferrin, lactoferrin (mother’s milk), ferritin
+ enzymes like the Fe-S complexes
Why does Fe concentration need to be regulated well?
IT CAN BE TOXIC: due to redox potential
-Ferrous ion leads to ROS formation via Haber-Weiss and Fenton reaction, this results in cell damage
HENCE: Fe needs to be stored and transported in ferric state (3+) bound to protein (ferritin)
What is the normal value of Fe in the body + where is it found? SOSARA
Total body Fe: 3-5g
- 70% in erythrocytes
- hepatocytes (Fe storage cells)
- skeletal muscle
!! 25-30 mg is needed for erythropoiesis and this is usually supplied by recycling of senescent RBCs
How much is daily iron intake from diet
Daily requirements from diet = 8mg - 20mg
!! this changes in diff people - in order of who should be getting the most iron from highest to lowest:
-pregnant women 27mg
-adult women 18mg (menstruation loss)
-adolescents (growth spurs)
-infants 11mg
-adult men 8mg
THE IRON CYCLE
INPUT:
-absorption of diet Fe (1-2 mg) from enterocytes
-Fe recycled from aged RBC by macrophages (in spleen and liver)
STORAGE:
-hepatocytes (can then either abdorb or mobilise Fe as needed)
-plasma Fe3+ transferrin (3mg)
OUTPUT:
-skeletal muscles
-erythropoiesis (25-30mg)
-PASSIVE LOSS: menstruation in women, skin exfoliation, urine and feces (1-2mg)
!! daily diet intake = daily passive loos
what is the bioavailability of Fe
- HEME IRON: high bioavailability (oysters, bef, liver, tuna, beef)
- NON HEME IRON: low bioavailability, its absorption is strongly influenced by other food components (beans, legumes, lentils, dark chocolate, nuts)
What factors affect the absorption of iron
Ascorbate and citrate –> enhacement (solubilise the metal in the duodenum) - eg squeezing lemon on meat
Calcium –> inhibitor (eg, drinking milk while eating meat)
Describe the absorption of exogenous iron
IN ENTEROCYTE:
1. heme Fe2+ enters enterocyte (unknown mechanism) and is mobilised by HO-1
- Non heme Fe enters enterocyte by first being reduced from Fe3+ (transferrin bound) to Fe2+ via CytB, and then passing through DMT1 (requiring H+ ions hence an acidic pH).
- Inside the cell, Fe2+ from both sources is bound onto ferritin
- AT THE LEVEL OF THE NON LUMINAL MEMBRANE:
- hephaestin (membrane bound ferroxidase) oxidises Fe2+ to 3+
-Ferroportin channel transports it to the blood where it forms the Fe3+ transferrin complex
How is Fe transported in the blood + what form does it exist in in cells (and reason why)
Fe2+ is almost insoluble and Fe3+ is soluble
-in blood plasma transferrin protein creates a complex with Fe3+ for its transport to tissues that either use it or store it –> hence outside the cells iron is ferric
-in order to be absorbed into cells Fe3+ is reduced to Fe2+, so inside cells the iron exists as ferrous
describe the role of transferrin
carries Fe3+ in the blood to ensure the iron remains soluble under physiological aqueous conditions and prevents it from participating in redox reactions
!! produced in liver
Describe the structure and role of ferritin
-universal intracellular (cytosolic) protein that controls the store and release of iron
-GLOBULAR protein: 24 subunits form a nanocage with a hollow center in the middle to accommodate ferric iron
what is another protein other than ferritin that can hold iron
HEMOSIDERIN: insoluble product of partial lysosome degradation of ferritin –> however it’s not as important bcos it releases the iron more slowly than ferritin does
Describe the process of iron uptake from the plasma to a desired cell
- Iron in plasma is present in the form of Fe3+ transferrin complex
- Tf-Fe3+ binds to TfR1 (receptors) on cells membrane and is internalised by clathrin mediated endocytosis
- combination of vesicle with an endosome + import of H+ ion to make contents acidic -> this allows Fe3+ to be liberated from Tf
- Fe3+ is reduced by STEAP to Fe2+
- Transport via DMT1 from endosome to the cytoplasm –> inside the cell it binds to Apo-ferritin (ie free ferritin) to form the FERRIC ferritin complexes
- Apo-TF (meaning Tf which no longer has Fe3+ bound to it) is recycled back into the plasma to form more complexes
regulation of Fe balance at a CHEMICAL level
PRIMARILY BY HEPCIDIN:
-Released by liver when Fe3+Tf is too high
-travels to enterocytes and induces internalisation and degradation of ferroportin -> this decreases the amount of Fe3+ being released into the bloodstream
!! the actual release of hepcidin is regulated at the transcriptional level using the HAMP gene:
-induced transcription through production of BMP6 by sinusoidal hepatocytes and by a large TF-Fe3+ conc
-decreased transcription during high erythrocyte activity (hypoxic conditions - release of HIF and EPO hence more Fe needed for heme in new erythrocytes)
