Iron Metabolism & Absorbtion Flashcards
What is Fe used for?
Readily exchanges e⁻, ideal catalyst for redox rxns, important role in e⁻ transport chain, O₂ transport, heme, stored in ferritin, myoglobin & enzymes
Where is Fe stored?
Much in RBCs some stored in ferritin, myoglobin & enzymes
What regulates bodies Fe content?
Modulating absorption (intestine)
What is the regulated pathway for Fe excretion?
There isn’t one
What does too much Fe do?
It’s interaction w/ O₂ can promote cellular damage
What is the total amount of Fe found in the body and how much is in RBCs?
3-5 g total, 2.7 g in RBCs
How much Fe is needed daily to support Hb production?
25 mg
What is the distribution of Fe in a normal man?
Hemoglobin: 67%
Storage Fe: 27%
Myoglobin: 5%
Fe-requiring proteins: 1%
In what forms does Fe exist?
Fe2+ (ferrous) Fe3+ (ferric)
In what forms does Fe exist?
Fe²⁺ (ferrous) Fe³⁺ (ferric)
What is ferritin, its location, and purpose?
Intracellular protein found in most cells that binds thousands of Fe3+/molecule
What is ferritin, its location, and purpose?
Intracellular protein found in most cells that binds thousands of Fe³⁺/molecule
Where is excess Fe mainly stored?
Liver, lunges, pancreas
What are the Fe transport proteins?
Ferrireductase, DMT1 (divalent transporter-1), Hephaestin, Ferroportin
In what form is dietary Fe?
Fe³⁺ (ferric)
What reduces ferric Fe to the ferrous form?
Dcytb (duodenal cytochrome-like b, Fe³⁺→Fe²⁺, ferric→ferrous
What reduces ferric Fe to the ferrous form?
Dcytb (duodenal cytochrome-like b, Fe³⁺→Fe²⁺, ferric→ferrous
What transports Fe outside the cell into the blood?
Ferroportin, basolateral surface → blood
What does ferroportin require to perform transport?
Ferroxidase (Hephaestin)
What carries Fe from the blood to the bone marrow?
Transferrin
What must first happen for Fe to be transported by transferrin into the bone marrow?
Fe must be changed from ferrous to ferric, Fe³⁺→Fe²⁺
What must first happen for Fe to be transported by transferrin into the bone marrow?
Fe must be changed from ferrous to ferric, Fe³⁺→Fe²⁺
What does transferrin do?
Binds 1-2 Fe³⁺/molecule w/ high affinity and carries Fe blood → tissues in a non-toxic form
What size and what type of protein is transferrin?
76 kDa serum glycoprotein
Describe tranferrin-receptor mediated endocytosis?
Transferrin binds Fe³⁺→ transferrin binds transferrin-R (TfR)→ endocytosed into endosome w/ clathrin coat→ clathrin coat removed→ proton pump ↓ pH to 5.5→ Fe released→ endosome fusses with cell exterior→ pH ↑ to 7.4→ TfR releases transferrin
What is the “kiss & run” hypothesis?
The idea that the TfR mediated transfer of Fe to the MT is so efficient that the endosome briefly docks “kisses” the MT transfers Fe directly & leaves “runs”, No cytoplasmic transport protein needed
What is the function of Steap3 ferroreductase?
Reduces Fe³⁺→Fe²⁺ in the endosome
What is the function of DMT1?
Transports Fe²⁺ out of endosome
What are causes of Fe deficiency?
Insufficient dietary Fe, menstration, Aspirin abuse
What are symptoms of Fe deficiency?
Gi tract ulcers, hypochromic microcytic anemia
What is the treatment for Fe deficiency?
Dietary Fe supplement
What are causes of Fe overloading?
Hereditary hemochromatosis, repeated blood transfusions (conditional Fe overloading)
What is the clinical definition of hereditary hemochromatosis?
Organ dysfuntion due to Fe orverload
What is the genetic definition of hereditary hemochromatosis?
Autosomal recessive mutation in HFE gene
What is the functional definition of hereditary hemochromatosis?
Malregulation of Fe uptake & export by entreocyte
What is the clinical presentation of hereditary hemochromatosis?
Elevated total body Fe w/ cell injury, liver damage, diabetes, heart failure, >400ng/mL, visible Fe overloading in liver
What is the function of the HFE protein and where is it found?
Binds transferrin-R
What is the role of HFE in hereditary hemochromatosis?
Mutation of HFE causes hereditary hemochromatosis
What is the treatment for hereditary hemochromatosis?
blood letting 1 unit blood/week up to 80 weeks → 1 unit/every other month, ExJade
What does ExJade do and what are its side effects?
Fe chelator, can cause nephrotic syndrome & death
What is the role of Hfe in signal transduction?
It is bound to Tfr1 until Fe competitively outbinds it → Hfe binds Tfr2 → induces hepcidin expression
What the relationship b/t Fe levels and hepcidin expression?
Fe replete= ↑ hepcidin
Fe deplete= ↓ hepcidin
What is the role of Hfe in signal transduction?
It is bound to Tfr1 until Fe competitively outbinds it → Hfe binds Tfr2 → ↑ hepcidin expression
Describe the role of bone morphogenic protein in hepcidin signaling?
↑Fe= ↑BMP6, BMP binds BMPR→R-SMAD binds SMAD4→ SMAD complex binds hepcidin promoter→ ↑ hepcidin
What is juvenile hemochromatosis?
Fe overloading disease that manifests in the 2nd decade of life
What is the role of hemojuvelin (HJV) in juvenile hemochromatosis?
↓HJV→ ↓BMPR effectiveness, Hemojuvelin is co-receptor for BMPR that enhances BMPR activity
What is the role of hepcidin antimicrobial peptide (HAMP) gene in juvenile hemochromatosis?
↓HAMP→ ↓hepcidin, HAMP makes hepcidin, rare condition
What is the cause of non-hereditary hemochromatosis?
Blood transfusions
What is the treatment for non-hereditary hemochromatosis?
ExJade
What does the transmembrane serine-protease (TMPRSS6) do and where is it made?
↑TMPRSS6→ ↓HJV, made in the liver
