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The Molecular Biology of Human Iron Metabolism

William E. Winter MD, Lindsay A. L. Bazydlo PhD, Neil S. Harris MD
DOI: http://dx.doi.org/10.1309/LMF28S2GIMXNWHMM 92-102 First published online: 1 May 2014

Abstract

Iron is one of the most important nonorganic substances that make life possible. Iron plays major roles in oxygen transport (eg, hemoglobin; ~67% of total body iron [TBI]), short-term oxygen storage (eg, myoglobin; ~3.5% of TBI), and energy generation (eg, cytochromes; ~3% of TBI).1 Iron also serves vital roles in various nonheme-containing enzymes (~2% of TBI). Figure 1 lists heme-containing and nonheme iron–containing proteins. TBI is controlled by the rate of iron absorption; there are no physiologic mechanisms to excrete excess iron.

Iron deficiency has many adverse consequences, including anemia, and in children, behavioral and learning disorders.24 Iron excess is toxic to the body, harming the heart, liver, skin, pancreatic islet beta cells, bones, joints, and pituitary gland. Maintaining proper iron balance is essential for maintaining homeostasis and health.

TBI in adults normally ranges between 3.5 and 5.0 g.5 A total of 75% of TBI is functional, and 25% is stored within cells as ferritin or hemosiderin. Ferritin contains 24 subunits of light chains (L chains; 19.7 kDa) and heavy chains (H chains; 21.1 kDa). The L chains are encoded on chromosome 19q13.33 and are 175 amino acids long. The H chains are encoded on chromosome 11q1 and are 183 amino acids long. Each ferritin molecule can contain as many as approximately 4500 ferric ions. Because the major role of iron is in hemoglobin synthesis, this review will focus on iron, iron transport, and hematopoiesis.

Keywords:
  • bone morphogenetic protein
  • ceruloplasmin
  • divalent metal ion transporter-1
  • ferritin
  • ferroportin
  • hemochromatosis
  • hemojuvelin
  • hepcidin
  • hephaestin
  • HFE
  • iron
  • transferrin
  • transferrin receptor
  • total body iron
  • Abbreviations

    BMP
    bone morphogenetic protein
    CCL2
    chemokine (C-C motif) ligand 2
    CXCL8
    C-X-C motif chemokine 8
    DAMP
    danger (or damage)-associated molecular pattern
    GDF-15
    growth differentiation factor-15
    HAMP
    hepcidin (hepatic) anti-microbial peptide
    HCP-1
    heme carrier protein-1
    HFE
    hemochromatosis
    HIF
    hypoxia-inducible factor
    HIF-2A
    hypoxia-inducible factor-2 alpha
    HJV
    hemojuvelin
    HRG1
    solute carrier family 48 (heme transporter), member 1
    IL-6
    Interleukin-6
    IL-6R
    interleukin-6 receptor
    IRE
    iron-responsive element
    IRP
    iron regulatory protein
    JAK
    Janus kinase
    MAPK
    mitogen-activated protein kinase
    PAMP
    pathogen-associated molecular pattern
    PRR
    pattern recognition receptor
    RBC
    red blood cell
    SLC11A2
    solute carrier family 11 (proton-coupled divalent metal ion transporter), member 2
    SLC40A1
    solute carrier family 40 (iron-regulated transporter), member 1
    SLC46A1
    solute carrier family 46 (folate transporter), member 1
    SMAD
    a “mothers against decapentaplegic” homolog
    STAT
    signal transducer and activator of transcription
    STEAP-3
    six-transmembrane epithelial antigen of the prostate-3
    TBI
    total body iron
    TfR1
    transferrin receptor 1
    TfR2
    transferrin receptor 2
    TWSG1
    twisted gastrulation protein homolog 1
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