Iron Metabolism Flashcards
Iron
Iron
-Essential Nutrient
*Catalytic component of enzymes
*Required for O2 delivery and utilization (Hb &
myoglobin)
- Toxic when it accumulates too much
- Intake too high
- Hereditary hemocromatosis
- Dietary requirements low
* Efficiently reutilized in body
* Normal elimination minimal
-Iron Deficiency (if too little, it’s problematic too…see other slide)
Iron Deficiency
- Inadequate dietary intake
- Blood loss (obvious or occult)
- Rapid growth (fetus or infant)
- Iron deficiency anemia is common
Properties of Iron
-Two oxidation states (Fe3+ Ferric and Fe2+ Ferrous)
-Involved in redox reactions that generate reactive oxidation species; e.g., Fenton reaction:
1)Fe2+ + H202 –> Fe3+ + OH(radical) + OH-
2)Fe3+ + H202 –> Fe2+ + OOH(radical) + H+
-FeCl3 and FeSO4 - soluble at acidic pH, insoluble or virtually insoluble at alkaline pH
(The Ferric Fe3+ will be in the FeCl form, while the Ferrous Fe2+ will be in FeSO4 form. Both of these salts will be soluble at acid pH, but they will be virtually insoluble at alkaline pH. This is important, because the stomach is acid and the pH stays acidic in duodenum (where most Iron is absorbed) allowing absorption; if it were alkaline, you would get very little iron absorption)
Functions of Iron
Lots of different proteins require iron in the form of HEME.
These USE HEME and allow for:
- O2 transport and release (hemoglobin and myoglobin)
- Reactions involving O2 (Catalase and Lactoperoxidase which eliminate H2O2, p450 heme proteins which detox of drugs/steroids)
- Electron transport (cytochrome c, aa3, b5 which transfer electrons)
- Guanylate cyclase (cGMP synthesis, TCA cycle)
The following uses 4Fe 4S:
-Aconitase (for TCA cycle, but also for a role that requires 4Fe 4S)
These use Fe:
- Transferrin (transports Fe in blood)
- Lactoferrin (transports Fe in milk)
- Ferritin (storage of Fe)
- Hemosiderin (it is a Ferritin degradation product that puts particles of iron in different tissues indication overload and has effects)
Dietary Iron (recommended daily allowance)
10 to 25mg/day (range of daily recommended value)
- GENERALLY speaking, 8 to 11mg/day is required for male and females
- during pregnancy 27mg/day is required
- during female puberty (14 to 18 years) and menopause (19 to 50 years) women lose iron in blood during period so they require 15mg and 18mg of Fe respectively, but after 51 years it goes down since they stop having period/losing blood
Iron absorption by enterocytes
All these proteins are INTEGRAL membrane proteins
The APICAL surface of enterocyte/brush-border (facing lumen/interiior of duadenum/intestine) has “Ferric reductase = converts Fe3+ to Fe2+” right next to “Divalent Metal Transporter 1 (DMT1)” which allows the Fe2+ (and other divalent metal ions) to pass through enterocyte membrane, entering the cell.
If a lot of Fe2+ enters the enterocyte cell, it will be stored in “Ferritin” in the “Fe3+ form” inside the cell
The rest will continue down the cell to enter the blood.
The BASOLATERAL SURFACE is the side of enterocyte that faces the interstitual fluid/interacts with the capillaries of small intestine. This end of enterocyte contains “Ferroportin=transports the Ferrous/Fe2+ outside of the cell” and it is close to “Hephaestin=oxidation site that faces interstitial space and converts the Fe2+ that just left the cell into Fe3+”
Ferric Reductase
- Linked to cytochrome b
- Reduces Fe3+ to Fe2+
- Apical surface of enterocyte
- Reduction coupled with transport (it is next to the DMT1, which will allow the Fe2+ formed by this enzyme to enter the entrocyte cell)
Divalent metal transporter 1 (DMT1)
- Proton-coupled transporter of Fe2+ (not Fe3+), as well as other divalent metals (this means you need environment to be acidic, because a proton has to enter the cell along with the Fe2+/other divalent metal)
- Apical surface of enterocyte
-Mice lacking DMT1 have severe iron deficiency
(**so DMT1 is VERY IMPORTANT for UPTAKE OF IRON)
Ferritin
- Intracellular iron binding protein
- Sequesters iron in shell of ferritin subunits
Ferroportin
-Transports Fe2+ to extracellular fluid
Hephaestin
- Copper ferroxidase (Fe2+ —> Fe3+)
- Integral membrane protein on basolateral surface
- Acts with ferroportin to transport iron
- ***This protein is important because iron must be in Ferric/Fe3+ form to bind to Transferrin protein and be transported in the blood)
Hepcidin
- This is a small peptide that is made in the liver
- It is a primary regulator of iron absorption
- It Inhibits iron absorption (ferroportin level)
(so Hepcidin regulates the activity of ferroportin to regulate the iron absorption)
Transferrin
- Iron binding protein in blood
- Specific for Fe3+
Ceruplasmin
- Soluble copper ferroxidase in plasma (so Ceruplasmin is a soluble protein that circulates in the blood)
- Maintains iron in oxidized state (Ceruplasmins makes sure that any Ferrous Iron that is free in blood becomes oxidized to Ferric form so that it can be bound to Transferrin and get transferred to tissues)
(The copper in the blood is usually transported by albumin, and it plays catalytic role. So copper is necessary in body as well)
HEME uptake by enterocytes
- Heme is taken up by “Heme Transporter (HT)”
- Iron removed by “heme oxygenase (HO)”
-Iron incorporated into ferritin (in Fe3+ form to remain in cell if excess iron for storage)
OR
-Iron transported to blood by “Ferroportin”
(Ferroportin is next to “hephaestin” which immediately reduces the Fe2+ that came out of cell into the blood into the Fe3+ form so that it can be transported in the blood)
