L15 Iron Metabolism Flashcards
What are 6 things iron is need for?
- Metabolism of xenobiotic compounds and drugs (CYP450)
- Respiration (cytochromes, FeS clusters)
- dNTPs synthesis (ribonucleotide reductase)
- Oxidative stress: (catalase etc)
- Oxygen Transport (hemoglobin)
- Oxygen Storage (myoglobin)
How much iron does the body usually contain in grams?
What are the amounts in grams and %s of iron in use, in circulation, and in storage?
The body usually contains 4g of iron
- 75% (3g) are in use, (2.5g in HGb, .5g in other proteins)
- 4mg are in circulation
- 25% (1g) is in storage
What is iron balance?
How is iron lost?
How much iron is absorbed and lost each day?
Iron Balance = Iron absorption - Iron Losses
Sloughing od dead cells is the body’s only mechanism for losing iron
1-2mg are absorbed and lost each day. Only the amount needed to replace what was lost is absorbed in the diet.
What are the 4 types of dietary iron and their levels of bioavailability?
What factors improve or diminish bioavailabilty?
Heme iron>> Ferrous (Fe2+)> Ferric (Fe3+)> Elemental iron (Fe0)
- An acidic environment improves iron availability. So proton pumps and antacids decrease availability.
- Achlorhydria also decreases availability.
- Heme iron is most easily absorbed (5-35% amount consumed is absorbed) and is found mainly in meat.
Non-heme iron:
- Ferrous iron (Fe2+) is the second most bioavailable but is less abundant. Ferrous iron is what is found in iron supplements.
- Ferric iron (Fe3+) is more abundant than ferric but less bioavailable because of low solubility.
- Elemental Iron (Fe0) is also insoluble at physiological pH and is the least available. It is used to fortify foods.
What prevents ferrous iron (Fe3+) from becoming insoluble in the duodenum?
Fe3+ binds mucins, citrate, glucose or amino acids. In this chelated form it will remain in solution even at the more alkaline pH of the duodenum (it would be insoluble otherwise).
What are enhancers of non-heme iron absorption and how do the work?
- Reducing molecules (e.g. Vitamin C): Reduce Fe3+ to the more soluble Fe2+ and from soluble complexes with Fe2+
- Amino acids (from meat or fish): form soluble complexes with Fe2+
- Acidic Foods: increased acidity improves solubility of Fe0 and Fe3+
What are 5 inhibitors of iron absorption?
Molecules that form insoluble complexes with Fe2+:
- Phytates (in grains and legumes)
- Polyphenols (tannins in coffee, tea)
- Phosphates/phosphoproteins: (egg yolk)
- Oxalate: (spinach
note: 3 & 4 also make complexes with Fe3+
Other inhibitors:
- Zn2+ and Ca2+: Compete with Fe2+ for absorption
How is dietary iron absorbed?
Heme and non-heme Fe are absorbed
by separate carriers at the enterocytes of
the duodenum and upper jejunum.
- On apical side of enterocytes, heme iron is taken up in tact and then degraded by heme oxygenase to release iron inside the cell.
Non-heme iron is absorbed by DMT1, a Fe2+ specific carrier. Another apical protein reduces Fe3+ in the gut to Fe2+ so that it can be transported by DMT1.
- Cytosolic iron is then bound by iron carrier proteins, to be used by different iron containing proteins, stored, or exported into circulation.
- Basolateral surface: Ferroportin (FPN) exports iron into the blood and is the only known iron exporter.
Why is iron always associated with a carrier protein and store/transported in the oxidized (Fe3+) state?
What is the fenton reaction?
Unbound iron (ferrous form only, Fe2+) is toxic because
it non-enzymatically catalyzes the formation of the
highly destructive hydroxyl radical (OH .) in the Fenton Reaction:
Fe2+ + H2O2 Fe3+ + OH- + OH.
Hydroxyl radicals are damaging to all cellular components. When iron is bound to a protein, it is unable to catalyze the fenton reaction.
Fe3+ is safe with or without a carrier protein while Fe2+ is only safe with a carrier protein.
What is transferrin and what does it do?
What are the different forms of transferrin?
Transferrin = abundant serum
protein which binds Fe3+ (ferric iron).
Transferrin → Iron transport
Transferrin can bind two Fe3+ atoms.
-0 iron = apotransferrin.
-1 iron = monoferric transferrin
- 2 irons = diferric transferrin.
- Under normal circumstances, only
about a third of transferrin iron sites
contain iron (33% saturation).
Transferrin transfers iron from the diet or degraded RBCs to growing cells that need iron.
How does iron get into cells from circulation?
Only iron bound to transferrin can get into cells and there must be 2 iron bound to transferrin (diferric transferrin).
Diferric transferrin binds to cell surface receptors present on all growing cells called transferrin receptors (TfR) which only bind diferric transferrin.
The complex endocytoses and forms an endosome.
Iron is released from the endosome for storage or use.
Apotransferrin (Apo-Tf, was diferric transferrin) returns to circulation and the Transferrin receptor (TfR) returns to the plasma membrane.
How is iron stored?
What is the best test to assess body iron stores?
Where is the most iron stored?
- *Ferritin** is an intracellular protein used to store
iron. Its subunits form a hollow pore that allow iron atoms to move into the cavity for storage, preventing the fenton reaction.
The serum ferritin level reflects the level of iron stored in the body.
It is found in all cells, but it is especially
prominent in the macrophages of the liver, spleen
and bone marrow.
Hemosiderin is another form of ferritin
that has been partially modified in
lysosomes. It contains 30% more stored
iron than ferritin In humans it is found
ferritin. humans, in conditions of iron overload.
How is iron exported out of cells?
What cells are capable of exporting iron?
Ferroportin is a membrane iron carrier which moves iron out of the following cells into circulation (NOT out of the body!)
Only 4 cells have ferroportin and are capable of exporting iron:
- Macrophages: export iron from RBC degradation
- Hepatocytes: export from storage
- Duodenal enterocytes: export from diet
- Placental trophoblasts: export iron to the embryo
ferroport**in is the _**port** for iron to depart_**
How is iron export regulated?
Hepcidin, produced by the liver, controls iron absorption and mobilization. Hepcidin is secreted into the plasma, where it circulates until it is filtered by the kidney.
- *Hepcidin functions by binding ferroportin**, which
- *induces** the internalization by endocytosis and the
- *degradation of ferroportin**
Thus, hepcidin prevents the release of iron from the
cells containing ferroportin.
What are the condition when hepcidin is low or high?
What occurs with hepcidin deficiency and what disease can this happen in?
Low hepcidin: (low Fe, low O2)
-ferroportin is high =
-Increased iron export from enterocyte = (increased absorption).
- Increased iron export from macrophages and
hepatocytes.
High hepcidin: (inflammation, high Fe)
-Ferroportin is low =
- Decreased iron export from enterocyte (decreased absorption).
- Decreased iron export from macrophages and
hepatocytes (increased iron stores).
Hepcidin deficiency, as in some cases of
hereditary hemochromatosis, results in uncontrolled
release of iron from macrophages and duodenal
enterocytes, thus causing tissue iron overload and organ damage (increased iron levels lead to generation of
hydroxyl free radicals).
