IRON Flashcards
What type of metal is Iron?
Transition metal
What defines a transition metal?
They can assume multiple oxidation states
What does the body use Iron for?
For oxidation-reduction reactions and electron transfer
What is the reduced form of iron?
Ferrous 2+
What is the oxidized form of iron?
Ferric 3+
At what pH will ferrous begin to precipitate out?
Around 6-6.5
At what pH will Ferric begin to ppt out?
Around 2.5-3
Why is Ferrous more bioavaible than ferric?
Because it is more soluble in lower pH levels (when it is absorbed in the small intestine, the pH levels are pretty low and and Ferric ppt out not Ferrous.)
Where is Iron located in the body?
2/3 in hemoglobin & Myoglobin Heme enzymes Non heme enzymes Intracellular labile iron transferrin ferritin/hemosiderin
What is the function of Iron in hemoglobin and myoglobin?
Binding and transport of Oxygen
What is the function of Heme enzymes?
Electron transport
What is the function of non heme enzymes?
Oxidative metabolism
What is the function of intracellular labile iron?
Gene expression
What is the function of transferrin?
Transport
What is the function of Ferritin/Hemosideerin?
Storage
How much Iron is found in women and males?
2.3 and 3.8
What is hemoglobin?
A tetrameric protein and in each of the subunits there is a heme group (heme = an iron locked into the center)
Briefly describe the process of Whole body Iron metabolism
Bone Marrow:
-Red blood cells are synthesized there and live for about 120 days in the circulation
Macrophages:
-Red blood cells are then eaten (phagocytosed) by marcrophages and recycle the iron back into the plasma.
Transferrin:
-Iron in the plasma will bind to its transport protein transferrin and most of it will travel back to the bone marrow or some will be stored in the liver.
What is the RDA for reproductive women and of that amount how much is absorbed?
18 mg and only 1-2 mg is absorbed in the small intestine.
How much iron is needed daily in the bone marrow?
24 mg
What is the only way to get rid of excess iron?
By blood loss
What are food sources of iron?
Heme iron:
-meat
Non heme:
-plant products
What is heme iron?
Fe is contained in a protoporphyrin ring
Found in meat in hemoglobin, myoglobin, and cytochromes
Highly bioavailable
What is non heme iron?
Can be organic chelates (e.g. ferric citrate, ferrous fumarate)
Can be constituents of biological molecules (e.g. iron-sulfur enzymes, ferritin)
Found in plants and meat
Relatively poorly bio available
What are nutrients that enhance Iron uptake?
Ascorbic acid (Vit. C) because it is a reducing agent (keeps it in the Ferrous form) Dietary Protein (Cys, His) Iron Chelation (e.g. heme) "Meat factor"
What are Endogenous factors that enhance Iron Uptake?
Enhanced erythropoiesis
Low iron stores
Hemochromatosis
HCl (stomach acid) because it keeps Ferrous soluble
What factors inhibit Iron uptake?
Phytic acid Oxalic acid Polyphenols (cofee and tea) high iron stores infection/inflammation lack of stomach acid
What does DMT1 stand for?
Divalent Metal Transporter 1
What is the main function of DMT1?
Transport Iron into the intestinal cell (enterocyte)
What is the tissue distribution of DMT1?
ubiquotous; abundant in duodenum
Where is DMT1 located?
Apical surface of enterocyte
What is the structure of DMT1?
Transmembrane protein
How is DMT1 regulated?
induced by iron deficiency
What are interesting facts of DMT1?
Mutations in DMT1 lead cause anemia
DMT1 first discovered in rodents and with anemia
What is the official gene name for DMT1?
Slc11a2
What is Dcytb and does it stand for?
A ferrireductase; Duodenal cytochrome B
What is the main function of Dcytb?
Reduces Ferric to Ferrous so it can be transported by DMT1
In what tissue is Dcytb distributed in?
duodenum, spleen, liver, brain
How is Dcytb regulated?
Induced by Iron deficiency
Interesting fact of Dcytb?
It uses ascorbate to provide reducing equivalents
What is ferroportin?
An iron-export protein
In what tissues is Ferroportin distributed
duodenum, spleen, liver, placenta
How is ferroportin regulated?
Induced by iron deficiency (intenstine) but by iron loading (macrophage)
What is the main whole body regulating point of entry of iron into the body?
Ferrportin
What is essential for iron export?
Ferroportin
What is hephaestin’s main function?
A ferroxidase, it oxidizes Ferrous to Ferric so it can bind to transferrin
What is the structure of hephaestin?
cystolic protein with single transmembrane domain
In what tissues is hephaestin distributed in?
Duodenum, lung, kidney,
A mutation in hephaestin may lead to what?
Anemia
How is hephaestin regulated?
Induced by iron deficiency (intestine)
The bone marrow is the site of what?
Erythropoiesis
How does the bone marrow get iron?
From only transferrin via the transferrin receptor
How is iron metabolized in erythroid cell
- Transferrin receptor TfR1 binds Fe-loaded transferrin (Fe-Tf) at the cell surface
- Fe-Tf bound to TfR1 is internalized into endosomes in the cell
- Fe3+ is reduced to Fe2+ which is transported into the cyotsol via DMT1
- Fe is taken up chiefly by mitochondria for heme synthesis
- TfR1-Tf complex recycles back to cell surface
- At cell surface, TfR1 releases Tf, which is free to bind more Fe and cycle again.
What is eALAS?
Erythroid Amino Levulinic Acid synthase
-the rate limiting enzyme in heme biosynthetic pathway
Where are macrophages found?
In the spleen, the liver and bone marrow
What system are macrophages known for?
Reticuloendothelial system (res)
What is the reticuloendothelial system?
Refers to macrohages of the liver, spleen, and bone marrow
Cells of the res ingest old RBCs and recycle their iron
The res also serves as a large storage reservoir for iron
What is Ferritin?
A large molecule found in cells that stores iron
What is the structure of Ferritin?
It has a H-ferritin (heavy chain) and L-ferritin (light chain) and has a core with some ferric oxyhydroxide (PO4)
Where is iron mainly stored?
In the liver
In genetic disorders of iron overload, where does iron mainly load?
In the hepatocytes of the liver
What is the liver’s job in body iron status regulation?
It senses body iron status and regulated body iron balance by producing the iron-regulatory hormone, hepcidin
In iron overload how is non-transferrin bound iron taken up into the liver?
Through Zip14
Where is iron balanced maintained?
At the point of absorption in the intestine
What hormone tells the body to stop absorbing iron?
Hepcidin
What is hepcidin?
A peptide hormone produced by the liver
How is Hepcidin induced?
By iron
How is Hepcidin shut off?
Shut off during iron deficiency
Where is hepcidin secreted into?
The circulation
When hepcidin is produced, where does it go and what does it bind to?
It goes to the intestine and bind to ferroportin causing it to degrade, so now iron is trapped in the cells.
Iron absorption is controlled by…
Hepcidin
How are serum iron levels controlled?
By hepcidin binding to ferroportin on marcopahges causing it degrade
Hepcidin inhibits iron release from where?
Macrophages and duodenum
Slide 59.
Common Motif
What are the biochemical functions of Iron?
Di oxygen transport
Oxidative and reductive transformations
Electron transfer
What is an example of oxidative and reductive transformations?
Cytochrome P450s
What is an example of electron transfer as a biochemical function of iron?
Electron transport chain - Cytochrome oxidase (Complex IV)
What is Cytochrome oxidase (Complex iv)
It catalyzes the final step in the electron transport chain, contains two heme groups and transfers electrons from oxygen to yield water.
What are screening methods of iron status?
Measuring functional iron in hemoglobin concentration
Measuring the saturation of TIBC/ transferring for tissue iron supply
Measuring serum ferriin in iron stores
What is the definitive method of measuring iron status?
Tissue biopsy: liver or bone marrow
Why is hemoglobin concentration is poor indicator of iron status?
Because
- RBCs have a long-life span (120 d)
- Low [Hb] levels can be due to many things such as folate/B12 deficiency, acute hemorrhage, and red cell disorders such as sickle cell, thalassemia.
Iron deficiency can lead to what?
Low Hb levels (anemia)
Why is [Hb] the most commonly used method to screen for iron deficiency?
Because it is fast, cheap, and easy to do.
When measuring Transferrin saturation what happens in iron def. and iron overload?
Def- low serum Fe and High TIBC/ferritin
Overload- high serum Fe and normal or ow TIBC/ferritin
What is the main disadvantage of measuring tansferrin saturation for clinical assessment?
Serum iron shows a pronounced diurnal variation
Plasma ferritin levels correlate strongly with what?
Tissue nonheme iron levels (storage iron)
Low plasma ferritin means what?
Iron def
High plasma ferritin means what?
- iron overload
2. inflammation, infection, chronic disease
Study slide 74
.
What is the single most nutrient deficiency in the world?
Iron
Causes of iron def
Blood loss - menstruation, gastrointestinal tract (food sensitivity, hookworms), genitourinary tract, respiratory tract, blood donation,
growth
prganancy
inadequate iron absorption- diet low in bioavaiable iron, impaired absrption due to intestinal malabsorpion, gastric surgery, hypochloryhydria, chrons
What is stage 1 Iron def?
Once iron stores are gone
What is stage 2 iron def?
Once your body cannot send enough iron to the bone marrow
Normal Functioning starts to decline before in iron deficiency even before what is evident?
Anemia
Consequences of iron def
Poor cognitive performance Diminished immune function reduced exercise ad endurance capacity anemia gowth retardation in children poor pregnancy outcomes
Study slide 84
.
Most iron overload is due to what>?
Herditary hemochromatosis (HH)
What is hereditary hemochromatosis?
Results from single point mutation C282Y in a gene called HFE which was identified in 1996
Where is HH more prevvelant?
In northern European descent
Clinical signs of HH begin to happen when…
40-60 yo and 20-40 g of excess iron has accumulated
Common feature of HH are
Lethargy abdomincal pain hepatic tenderness hepatomegaly arthropathy hepatocellular carcinoma diabetes melitus weight loss hypogonadism increased skin pigmentation (bronze color)
HH results from a decrease of what hormone?
Hepcidin
Cellular iron metabolism is regulated by
IRE/IRP interactions
What is the RDA for males and females?
8;18mg/day
