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Iron metabolism

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Iron metabolism Dr Artur S omka Department of Pathophysiology Collegium Medicum in Bydgoszcz Poland Ko ice, April 2016 – PowerPoint PPT presentation

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Title: Iron metabolism


1
Iron metabolism
  • Dr Artur Slomka
  • Department of Pathophysiology
  • Collegium Medicum in Bydgoszcz
  • Poland

Košice, April 2016
2
Iron at a glance
3
Human iron physiology
3 mg of Fe
Int J Hematol. 201193(1)14-20
4
Human iron physiology
5
Henry John Horstman Fenton Oxidation of tartaric
acid in presence of iron. J. Chem. Soc., Trans.
189465, 899-910
hydroxyl radical
DNA, proteins, lipids, carbohydrates
Cellular injury
6
Iron forms
Fe2
Fe3
7
Four general categories of iron-containing
proteins
Iron-containing nonenzymatic proteins
Heme-containing enzymes
Iron-sulfur enzymes
Nonheme proteins
8
List of selected eukaryotic hemoproteins
Electron transport
Gas binding
Transcription factors
The remaining metabolic processes
Front Pharmacol. 20145126
9
Four general categories of iron-containing
proteins
  • Hemoglobin
  • the major protein contained in mature RBCs,
  • the physiologic role of hemoglobin is transport
    of oxygen from the lungs to the tissues.
  • Mioglobin
  • the single-chain hemoprotein in muscle tissues,
  • the concentration of myoglobin in skeletal
    muscle is drastically reduced (4060) in tissue
    iron deficiency.

Iron-containing nonenzymatic proteins
10
Four general categories of iron-containing
proteins
In 1862, Felix Seyler identified the
respiratory protein hemoglobin.
26 December 1825 10 August 1895
11
Four general categories of iron-containing
proteins
In 1962, Max Perutz together with Sir John
Cowdery Kendrew (1917-1997) received the Nobel
Prize for Chemistry for their studies of the
structures of globular proteins.
Max Ferdinand Perutz, OM, CH, CBE, FRS 19 May
1914 6 February 2002
"The Nobel Prize in Chemistry 1962". Nobelprize.or
g. Nobel Media AB 2014. Web. 1 Apr 2015.
lthttp//www.nobelprize.org/nobel_prizes/chemistry/
laureates/1962/gt
Blood 20081123927-38
12
Four general categories of iron-containing
proteins
Myoglobin was the first protein described by
X-ray crystallography. (Nature 1958 181662-6)
Sir John Cowdery Kendrew, CBE 24 March 1917 23
August 1997
J Mol Biol. 2009392232
13
Four general categories of iron-containing
proteins
  • NADHcoenzyme Q reductase, succinatecoenzyme Q
    reductase and Rieske proteins
  • electron transport chain.
  • Mitochondrial aconitase
  • Krebs cycle (TCA cycle).
  • Ribonucleotide reductase
  • synthesis of DNA.

Iron-sulfur enzymes
14
Four general categories of iron-containing
proteins
  • Cytochromes
  • P450, A, A3, B and C - electron transport.
  • Catalase
  • decomposition of  H2O2 to water and oxygen.

Heme-containing enzymes
15
Four general categories of iron-containing
proteins
  • Transferrins
  •  deliver iron to cells via a receptor-mediated
    endocytotic process.
  • Ferritin
  • an iron storage compound.
  • Lactoferrin
  • an anti-bacterial function.

Nonheme proteins
16
Sum and substance of iron functions
  • oxygen transport and storage (hemoglobin and
    mioglobin),
  • DNA biosynthesis (ribonucleotide reductase),
  • production of nitric oxide (nitric oxide
    synthase),
  • cell cycle and differentation (transcription of
    genes),
  • electron transport (cytochromes),
  • brain functions (learning and memory),
  • retina function (retinal pigment
    epithelium-specific 65 kDa protein),
  • immunity (lactoferrin).

17
Iron in the brain
Positive iron staining is demonstrated by the
darkly stained oligodendrocytes in the
iron-sufficient brain on the right and
iron-deficient brain on the left
Pediatr Res. 200048(2)169-76
18
Myelinogenesis
Cerebellar white matter in 17-day-old normal iron
status rat
Areas of cerebellum in 17-day-old iron-deficient
rat
The faint blue staining (Luxol fast blue stain)
indicates poor myelination
Am J Pathol. 1986125(3)620-4
19
Iron and brain functions
  • myelinogenesis
  • iron deficiency ? reduction of myelination in the
    spinal cord (? nervonic acid).
  • functions of neurons
  • iron deficiency
  • reduction of cytochrome c oxidase (CytOx)
    activity  ? ? memory processes,
  • ? gamma-aminobutyric acid and ? glutamate
    (without affecting hemoglobin),
  • ? dopamine D2 receptor,
  • ? 5-hydroxytryptamine (serotonin).

20
 Source of iron
  • diet is the only source of iron for humans,
  • the normal diet should contain 1318 mg of iron
    per day,
  • only 1 mg of dietary iron is absorbed (even in
    ID absorption is only 24 mg),
  • two forms of dietary iron heme (15 of iron in
    regular diet) and nonheme (85 of iron in
    regular diet),
  • heme iron - mostly from animal products (red
    meat),
  • nonheme (inorganic) iron - mostly from plant
    foods.

21
 Source of iron
Dietary iron
22
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23
  Regulation of cellular iron metabolism
  • proteins involve in iron metabolism are
    regulated by the interaction of the iron
    regulatory proteins (IRPs - IRP-1 and IRP-2),
  • IRPs bind to iron-responsive elements (IREs) in
    the 5' or 3' untranslated regions of mRNAs
    encoding proteins involved in iron metabolism
  • transferrin receptor,
  • DMT-1 (divalent metal transporter 1),
  • ferritin,
  • ferroportin.

24
IRPs
? Iron
? Iron
  • IRPs bind to 5 IREs in ferritin and ferroportin
    mRNAs to repress translation,
  • and to 3 IREs in TfR1 mRNA to block its
    degradation.
  • IRPs do not bind to IREs, increasing synthesis of
    ferritin and ferroportin,
  • while promoting the degradation of TfR1 mRNA.

25
Ferritin
Ferritin was discovered in 1937 by V. Laufberger.
(Sur la cristallisation de la ferritine. Bulletin
de la Societe de chimie biologique.19371915751
582)
Ferritin molecule
H chain ferritin
Biochim Biophys Acta. 20101800(8)706-18
26
ferroxidase activity (Fe2?Fe3)
serum ferrritin
27
 Ferritin
? H
? L
  • TNFa,
  • interleukins1 and 6, 
  • interferon-?.
  • iron,
  • prostaglandins.

? H and ? L
  • TRH and T3, 
  • insulin and IGF-1,
  • oxidants.

28
 Ferritin and glucose
Effect of glucose on ferritin in cultured
pancreatic islets. Islets were maintained for 24
h in tissue culture medium containing either 1 mM
glucose or 20 mM glucose.
FASEB J. 19948(10)777-81
29
 Ferritin
  • the major function of ferritin is to limit
    Fe(II) available to participate in the generation
    of ROS,
  • serum ferritin is directly related to
    intracellular ferritin.
  • CLINICAL UTYLITY
  • test for diagnosing ID (15 µg/L),
  • an acute-phase protein ? patients with
    inflammatory disorders/liver disease may have
    normal or increased ferritin.

30
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31
Lancet. 2015
32
Serum ferritin - cutoffs
Lancet. 2015
33
 Ferritin in human disease
Int J Inflam. 20122012298405
34
 Ferritin in human disease
Rheumatology (Oxford). 200241(2)216-22/Ther
Clin Risk Manag. 20141133-43
35
 Ferritin in human disease
Fe2
L-DOPA
Ther Clin Risk Manag. 20062(4)465-75
36
Transferrins
  • nonheme iron-binding glycoproteins,
  • transferrin family
  • serum transferrin,
  • lactoferrin,
  • ovotransferrin (reptiles and birds),
  • melanotransferrin (p97, melanomas).

Serotransferrin
  • composed of 679 amino acids (79.6 kDa),
  • mainly produced in the liver (normal levels 2.5
    mg/mL).

37
Holo-form of serum Tf
Apo-form of serum Tf
Biochim Biophys Acta. 20121820(3)417-26
38
 Serotransferrin
The function of this protein is to transport iron
from the enterocytes, MPS, and hepatocytes to all
proliferating cells, especially to bone marrow.
? Iron deficiency anemia
? Iron overload, cirrhosis and protein
malnutrition
There are significant (17 to 70) diurnal
fluctuations in transferrin saturation.
39
 Transferrin receptor 1 (CD71)
Pharmacol Rev. 200254(4)561-87
40
 Transferrin receptor 1
  • can bind up to two molecules of transferrin,
  • expressed in all nucleated cells (mostly on
    proliferating cells),
  • binds two proteins critical for iron metabolism
    transferrin and HFE (human hemochromatosis).

It has been demonstrated that targeting of
transferrin receptor is effective in delivering
therapeutic agents to cancer cells. 
41
 Tf cycle (2-3 minutes)
J Cell Biol. 2003162(5)909-18
  • Zip14
  • TRPML1

Biochim Biophys Acta. 20121820(3)326-33
Nat Genet. 200537(11)1264-9
42
 HFE
ß2-microglobulin
43
 Transferrin receptor 2
44
Soluble transferrin receptor
45
Changes in sTfR concentration
Am J Hematol. 200883(11)872-5
46
DMT1/ DCT1/Slc11a2/ Nramp2
47
DMT1/ DCT1/Slc11a2/ Nramp2
Blood morphology of wild type mice.
Blood morphology of Slc11a2/ mice.
J Clin Invest. 2005115(5)1258-66
48
HEPCIDINThe milestone in iron metabolism
49
Discovery of hepcidin
50
hepatocyte
microbicidal activity
51
Hepcidins action
Proc Natl Acad Sci U S A. 200198(15)8780-5
Proc Natl Acad Sci U S A. 200299(7)4596-601
52
Hepcidins action
Hematology Am Soc Hematol Educ Program. 20112011
538-42
53
Hepcidinferroportin axis mediated regulation of
serum iron level
54
Ferroportin
hephaestin
ceruloplasmin
Cell Biosci. 2014419
55
Ferroportin (Fpn) is essential for
development of the mouse embryo, forebrain
patterning and neural tube closure.
A, C - wild-type mice B, D - Fpn1ffe/ffe mutant
mice Mutant embryos are delayed, and exhibit
exencephaly, microphthalmia and generalized
edema.
Development. 2010137(18)3079-88
56
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57
 Hepcidin synthesis
58
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59
 Hepcidin synthesis
HAMP gene 19q13.1
Preprohepcidin (84aa)
Prohepcidin (60aa)
Hepcidin (25aa) (2789.4 Da)
Hepcidin (20aa)
Hepcidin (22aa)
New forms 24aa, 23aa, 19aa
60
 Hepcidin synthesis
Hepcidin has been found only in vertebrates (may
be missing in avians).
61
 Hepcidin synthesis
Iron
Erythropoiesis
Hypoxia
Inflammatory reaction
62
Clin Chim Acta. 2010411(21-22)1565-9 
63
 Hepcidin synthesis
Prohepcidin can bind to and transcriptionally
regulate the expression of HAMP.
Biochem J. 2013451(2)301-11
64
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65
Serum hepcidin - reference ranges
Hepcidin
Blood. 2011117(25)e218-25
66
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67
Iron deficiencyKey facts
68
The numbers are staggering 2 billion people
over 30 of the worlds population are anaemic,
many due to iron deficiency, and in resource-poor
areas, this is frequently exacerbated by
infectious diseases. 
69
Cause-specific anemia prevalence for 1990 and
2010
Blood. 2014123(5)615-24
70
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71
IDA - etiology
72
IDA the main symptoms
Lancet. 2015.
73
Stages of advancing iron deficiency
J Acad Nutr Diet. 2012112(3)391-400
74
Review questions
Mary Louise Turgeon Clinical Hematology Theory
and Procedures
75
Review questions
  • The causes of anemia include
  • A. blood loss
  • B. impaired red cell production
  • C. accelerated red cell destruction
  • D. all of the above.

76
Review questions
  • 2. The clinical signs and symptoms of anemia can
    result from
  • A. diminished delivery of oxygen to the tissues
  • B. lowered hemoglobin concentration
  • C. increased blood volume
  • D. both A and B

77
Review questions
  • 3. Which of the following is a significant
    laboratory finding in anemia?
  • A. Decreased hemoglobin
  • B. Increased packed cell volume
  • C. Increased erythrocyte count
  • D. Normal erythrocyte indices

78
Review questions
  • 4. Anemias can be categorized into
  • A. hemolytic types
  • B. blood loss types
  • C. impaired production types
  • D. all of the above

79
Review questions
  • 5. The etiology of IDA is
  • A. nutritional deficiency
  • B. faulty iron absorption
  • C. excessive loss of iron
  • D. all of the above

80
Review questions
  • 6. Iron deficiency is still common in
  • A. toddlers
  • B. adolescent girls
  • C. women of childbearing age
  • D. all of the above

81
Review questions
  • 7. Most functional iron in humans is found in
  • A. the bone marrow
  • B. the liver
  • C.hemoglobin molecules of erythrocytes (RBCs)
  • D. the free hemoglobin in the circulation

82
Review questions
  • 8.In IDA, the erythrocytic indices are typically
  • A.MCV increased, MCH decreased, and MCHC
    decreased
  • B.MCV decreased, MCH decreased, and MCHC
    decreased
  • C.MCV decreased, MCH increased, and MCHC
    decreased
  • D.MCV decreased, MCH decreased, and MCHC normal

83
Review questions
  • 9. The peripheral blood smear demonstrates _____
    red blood cells in IDA.
  • A. microcytic, hypochromic
  • B. macrocytic, hypochromic
  • C. macrocytic and spherocytic
  • D. either A or B

84
Review questions
  • 10. In IDA, the
  • A. serum iron is severely decreased and the TIBC
    is increased
  • B. serum iron is decreased and the TIBC is normal
  • C. serum iron is normal and the TIBC is normal
  • D. serum iron is increased and the TIBC is normal

85
References available upon request
  • slomkaartur_at_gmail.com

86
THANK YOU
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