IRON

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Uses of Iron I - Heme Proteins

• Oxygen Carriers
• Hemoglobin, myoglobin
• Electron Transfer (ETC/ox phos)
• Cytochromes a, b, c
• (convert NADH, FADH2 into ATP energy)
• Metabolism of O2 Peroxides (R-OOH)
• Cytochrome P450 (drug metabolism)
• Catalase (degrades H2O2)
• NADPH oxidase (phagocytes)

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Uses of Iron II Iron-Sulfur Cluster Proteins

• Redox enzymes
• Succinate dehydrogenase (TCA)
• Xanthine oxidase (purine degradation)
• Non-redox Enzymes
• Aconitase (TCA)

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Uses of Iron III Single Fe-Containing Enzymes

• Monooxygenases
• Add OH to aromatic amino acids
  (neurotransmitter synth)
• tyrosine dopamine
• tryptophan serotonin
• Dioxygenases
• Synthesis of OH-lysine, OH-proline in collagen
• Used to crosslink collagen fibrils in connective
  tissue
• Enzymes containing Fe-O-Fe
• Ribonucleotide Reductase (makes deoxyribose)

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Iron toxicity

• Insoluble in body
• Fe3 (ferric) 10-17 M Fe2 (ferrous) 10-9 M
• Strong oxidizing agent (Fenton reaction)
• Fe2 H2O2 Fe3 OH OH-
• Fe3 O2 - Fe2 O2 ( repeat)
• Must be kept protein bound to keep it soluble
  reduce its toxicity
• Toxicity risk- hemochromatosis

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Fe in serum

• Regulated tightly by Fe status
• Transferrin is major carrier in the blood
• Cell must have Transferrin Receptor to take up
  use Fe
• Normal status Tf is 30 saturated with Fe
• Iron also found as serum ferritin

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Transferrin
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The transferrin cycle
Dmt1
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The transferrin cycle
Dmt1
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Iron Stores

• Major tissue sites are liver bone marrow/spleen
• Storage varies w/gender, age, diet, disease
• Storage form ferritin
• Cytosolic multimeric protein
• Reversible storage form

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Ferritin
x 24
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• Regulation of cellular iron metabolism
• Post-transcriptional control
• mRNA stability
• translation
• Regulated by the Iron Regulatory Proteins (IRPs)

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Iron metabolism

• Functions and toxicity of Fe
• Fe in serum- transferrin
• Cellular Fe metabolism
• Regulation of cellular iron
• Intestinal iron absorption
• Macrophage iron metabolism
• The Fe cycle
• Systemic control of iron metabolism- hepcidin
• Hemochromatosis

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Iron in the diet

• Heme and nonheme iron
• meats- primarily heme iron
• vegetables- primarily non-heme iron
• Bound to proteins
• Released by proteases (e.g. pepsin) and HCl
• Heme is taken up intact
• Non-heme iron is transported as Fe(II)

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Zn, Cu, and Fe Papers

• 1. Components of zinc transport.
• Liuzzi et al. 2005, Eide 2006
• 2. Levels and trafficking of intracellular metal
  ions.
• Outten and OHalloran, 2001
• 3. Copper transporters and their function.
• Puig and Thiele 2002, Nose et al. 2006
• 4. Regulation of mineral homeostasis-regulated
  protein trafficking.
• Petris et al. 2002
• 5. Use of model systems (e.g. yeast, nematodes,
  zebrafish) to identify mammalian iron
  transporters.
• Hentze et al. 2004, Donovan et al. 2000
• 6. Hormonal regulation of iron status- Hepcidin.
  
• Nemeth et al. 2004

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• Fig. 1. The phenotype of weissherbst (weh)
• Reduced hemoglobin
• Hypochromic anemia
• Not due to globin protein defects

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Fig. 2. The protein product of weissherbst
(weh)- ferroportin1
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Fig.3. Ferroportin1 is an iron exporter protein
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Fig. 4. Expression of the mammalian ferroportin
protein
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Iron metabolism

• Functions and toxicity of Fe
• Fe in serum- transferrin
• Cellular Fe metabolism
• Regulation of cellular iron
• Intestinal iron absorption
• Macrophage iron metabolism
• The Fe cycle
• Systemic control of iron metabolism- hepcidin
• Hemochromatosis

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Wheres the Iron in Body?(3 gm total)

• Hemoglobin 2000 mg
• Storage Fe 1000 mg
• Tissue Fe
• Myoglobin Fe 130 mg
• Enzyme Fe 8 mg
• Transport Fe (blood) 3 mg

Values are for a 70 kg adult male female values
lower
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Zn, Cu, and Fe Papers

• 1. Components of zinc transport.
• Liuzzi et al. 2005, Eide 2006
• 2. Levels and trafficking of intracellular metal
  ions.
• Outten and OHalloran, 2001
• 3. Copper transporters and their function.
• Puig and Thiele 2002, Nose et al. 2006
• 4. Regulation of mineral homeostasis-regulated
  protein trafficking.
• Petris et al. 2002
• 5. Use of model systems (e.g. yeast, nematodes,
  zebrafish) to identify mammalian iron
  transporters.
• Hentze et al. 2004, Donovan et al. 2000
• 6. Hormonal regulation of iron status- Hepcidin.
  
• Nemeth et al. 2004

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• Systemic control of iron status
• Systemic regulators
• Stores
• Erythroid
• Hypoxia
• Inflammatory
• Sites of action
• control intestinal uptake
• control release of iron from macrophages
• Hepicidin

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• Previous hepcidin studies
• Hepcidin is a 25 amino acid serum peptide
• Hep KO have increased Fe accumulation
• Hep overexpressors have decreased Fe
• Hepcidin is expressed in liver
• Hepcidin expression is induced by
• iron
• infection inflammation (IL-6)
• hypoxia
• erythropoiesis

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Hereditary hemochromatosis

• Disease of Fe overload
• Majority caused by mutation in HFE gene
• Most common genetic defect of Caucasians
  (1/400)
• Carrier frequency of 1/10
• People absorb store Fe too efficiently
• Dysregulation of intestinal Fe absorption
• Symptoms are of Fe toxicity
• Oxidative damage to tissues (esp heart and liver
  failure)
• Incr risk of atherosclerosis CVD
• Treat w/phlebotomy, Fe-chelators
• Why is this mutation so common?

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Genes causing hemochromatosis or other iron
overload conditions

• HFE
• Surface protein, function unknown
• Interacts with TfR
• Ferroportin
• Alleles with decreased hepcidin response?
• Tfr2
• Liver specific TfR
• Signaling to hepcidin expression?
• Hemojuvelin
• GPI-linked cell surface protein
• Activity affects hepcidin expression
• Hepcidin
• Ferritin H (IRE mutant)- hyperferritinemia
• Ceruloplasmin

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JBC 281 28494 (2006)
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