-Scandinavian “Iarn"
10/19/2006
Yuka Mitsuhashi
Overview
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History
Fact - chemistry
Function
Distribution
Functional and storage iron
Absorption
Homeostasis
Fe - mineral interaction
Storage Status
NUTR 650, 10/19/2006
History
• The ancient Greeks administered iron to their injured
soldiers to improve muscle weakness
• 18th century - Menghini shows that blood contains iron by
lifting dried blood with a magnet
• 1825 - hemoglobin iron content was determined to be
0.35%.
• 1832 – 1843 - Chlorosis was defined by low level of iron in
the blood and reduced number of red cells
• 1872 - Boussingault first described the nutritional essentiality
of iron
NUTR 650, 10/19/2006
History
• 1892 - Bunge describes special vulnerability of infants to iron
deficiency and notes that milk is a particularly
poor source of iron
• 1928 - Mackay shows that infantile anemia can be avoided by
use of iron fortified formula
• By 1960’s - Physiology and clinical nutrition largely completed
• 1990’s-present - molecular details of how iron metabolism is
regulated
NUTR 650, 10/19/2006
Facts
• 26th element in the periodic table
–
–
–
–
–
Chemical Symbol: Fe
MW = 55.85
Electron Configuration: 1s2 2s22p6 3s23p64s23d6
Fourth most abundant mineral O > Si > Al
Oxidation states = -2 to +6
• Readily interconverted, i.e. redox active
– very useful for redox chemistry in the body
– very dangerous chemistry
ADP - Fe3+ + O 2-• ---> ADP - Fe2+ + O2
ADP - Fe2+ + H2O2 ---> HO• + OH-
NUTR 650, 10/19/2006
Function
Flavoproteins
Transferrin
&
Others
Ferritin
&
Hemosiderin
Hemoglobin
Heme
Flavoproteins
2Fe-2S
4Fe-4S
Nzms
Other Nzms
Fe-sulfur
Nzms
Other Fe
Proteins
Fe-Containing
Proteins
Hemeproteins
Myoglobin
Cytochromes
Other Fe
Nzms
Iron
Activated
Nzms
Other Nzms
Other Nzms
NUTR 650, 10/19/2006
Function
• Oxygen Transport & Storage
– Hemoglobin
– Myoglobin
• Electron Transport & Energy Metabolism
– Cytochromes
– Fe-S proteins
• Substrate Oxidation & Reduction
– Iron dependent enzyme–
–
–
–
–
Ribonucleotide reductase
Amino acid oxidases
Fatty acid desaturases
Nitric oxide synthetase
Peroxidases
• Regulation of intracellular iron
NUTR 650, 10/19/2006
Distribution
Compound
Functional
Male (mg/kg)
Female
(mg/kg)
Hemoglobin
31
26
Myoglobin
4
3
Heme Nzm
1
1
Nonheme Nzm
1
1
Transferrin Iron
0.05
0.05
37 (74%)
33 (87%)
Ferritin
9
4
Hemosiderin
4
1
13 (26%)
5 (13%)
50
38
Total
Storage
Total
Body Total mg/kg
Handbook of Nutritionally Essential Mineral Elements
NUTR 650, 10/19/2006
Iron Requirement mg/day
Distribution
6
5
Fetus
4
3
Menstruation
2
1 Menstruation
Non gravid
Red Cells
Body Iron Loss
1st
2nd 3rd
Lactation
Postpartum
Trimester
NUTR 650, 10/19/2006
Whole body fluxes
Iron Intake (10-14mg→0.5-2mg)
Plasma Iron (transferrin)
Myoglobin (200mg)
Enzyme Iron (5mg)
Erythrocyte
Hemoglobin
(~2500mg)
Liver, Spleen
Bone marrow
Ferritin
Stores
Hemosiderin
(1500mg)
Iron Loss (1-2mg)
NUTR 650, 10/19/2006
Functional iron
Transferrin: Transport iron
• Single polypeptides composed of two iron
binding half-site motifs, ~679 aas, ~80 kD MW
• Carbohydrate-rich globular proteins
• Bind 2 Fe3+ and 2 HCO3
• Normally 25-50% saturated with iron
– Lactoferrin is iron binding protein in milk,plasma
and mucus secretion such as tears
– Ovotransferrin is iron binding protein in bird’s egg
white
NUTR 650, 10/19/2006
Storage Iron
Ferritin
• Major iron storage protein
• Apoferritin 24polypeptide units in
raspberry-like cluster
• Surrounds spherical cluster of hydrated
ferric phosphate within its hollow center
• Can contain up to 4000 Fe atoms
• Liver contains ~60% of ferritin in the body
• ~40% are found in muscles and the reticuloendothelial cells
• Two isoforms
- H subunit: 22kDa, 182aas, predominant in heart
- L subunit: 20kDa, 174aas, predominant in liver
NUTR 650, 10/19/2006
Storage Iron
Hemosiderin
• ~50% liver iron stores
• Reacts to ferritin antibodies - likely a degradation
product
• Insoluble, ~30% iron by weight
• Less available for mobilization
NUTR 650, 10/19/2006
Iron forms in diets
• Heme
– Iron-porphyrin prosthetic group
– Hemoglobin, myoglobin, cytochromes
– Other iron-containing enzymes are
~3% body iron
• Aconitase, peroxidases
– 5-25% are absorbed
– Exist as Fe2+
• Nonheme
– >85% of iron in foods is non heme iron
– 2-5% are absorbed
– Exist as Fe3+
NUTR 650, 10/19/2006
Absorption
Nonheme
1. Iron solublized and
ionized by stomach acid
2. Chelation with small molecular
weight compounds and mucin
3. Iron chelates pass through
unstirred water layer bind to
surface proteins and
are internalized
Heme
1. Protein digestion of
hemoglobin and
myoglobin releases heme
2. Heme transported as
such into the cell
4. Absorption all along
the small intestine, but
highest in duodenum
NUTR 650, 10/19/2006
Absorption
• Ferrous, Fe2+, most soluble = most
absorbable
• Each mechanism has 3 phases
– Iron uptake
– Intraenterocyte transport
– Storage and extraenterocyte transfer
NUTR 650, 10/19/2006
Absorption
Duodenal Mucosa
Duodenal Lumen
HemeProtein
Biliverdin
HFE
Heme
+
Polypeptides
Fe++
Fe++
Fe++
Mucin
DMT1
B3 integrin
Fe2+
Bilirubin
Bilirubin
CO
B2-microglobulin
Heme
Plasma
Fe3+
CO
Ferroportin
Fe2+
paraferritin
Mobilferritin
Fe2+
Ceruloplasmin
Fe3+
Transferritin
NUTR 650, 10/19/2006
Absorption
Iron uptake - Duodenal lumen to Duodenal mucosa
Factors affecting Iron Absorption
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Dietary Iron Content
Bioavailability of ingested iron
Body Iron Stores
Erythrocyte production rates
Iron Form
• Heme - from animal sources 2-3x more available
• Non-heme - solubility key, ~85% of dietary iron
– Gender, Men = 6% absorption; Women = 13%
NUTR 650, 10/19/2006
Absorption
Iron uptake phase
- Duodenal lumen to Duodenal mucosa
• Promotors
– Amino Acids
– Animal Proteins(for
heme)
– Ascorbic Acid
– Hydrochloric Acid
– Organic Acids
– Sugars
– Mucin
• Inhibitors
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–
–
–
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–
–
Carbonates
Calcium (for heme)
Egg yolk phosvitin
Fiber
Oxalates
Phosphates
Phytates
Plant polyphenols
Soy proteins
NUTR 650, 10/19/2006
Transferrin Receptor
Storage and extraenterocyte transfer phase
• Transferrin Receptor (Tfr)
– Mechanism for most cellular iron uptake
– 180-kDa glycoprotein
• 2 identical subunits
– Multiple regulators of transcription & translation
• Several metals (++), retinoic acid (-), & 1,25 Vit D3
• Phosphorylation
– Binds 1 transferrin
• High affinity binding
• Prefers diferric Tf > > apoTf
• Usually saturated due to normal Tf plasma concentration
NUTR 650, 10/19/2006
Intracellular iron metabolism and
homeostasis
Handbook of Nutritionally Essential Mineral Elements
NUTR 650, 10/19/2006
Homeostasis
•Iron Regulatory Proteins
- Regulate iron storage and metabolism
- Bind to iron response elements and regulate the synthesis of specific proteins
Low Iron High Iron
Yes
NO
Iron-Responsive
Element(IRE) bound by IRP?
Ferritin mRNA
3’
AAAn translation
5’
Ferritin
Ferritin mRNA Synthesis
3’ TfR mRNA
AAAn stability
5’
Transferrin Receptor TfR
(TfR) mRNA
synthesis
Repressed Activated
Increased Decreased
NUTR 650, 10/19/2006
Mineral Interactions
Cu
Zn
Fe
(-)
Mn
NUTR 650, 10/19/2006
Mineral Interactions
Fe-Cu interactions
• Cu deficiency causes iron accumulation because iron can’t
mobilize from tissues (Textbook)
• Cu-deficient male rats absorbed less Fe than Cu-adequate rats
and were severely anemic
(J. Nutr. 134:1953-1957, 2004)
• Dietary Copper Deficiency Reduces Iron Absorption and
Duodenal Enterocyte Hephaestin Protein in Male and Female
Rats
(J. Nutr. 135:92-98, January 2005)
• Current theory of Fe-Cu interactions
4Fe2+ + O2 + 4H+
4Fe3+ + 2H2O
(Plasma Cu-containing enzyme ceruloplasmin (ferroxidase1), Hephaestin)
NUTR 650, 10/19/2006
Mineral Interactions
Fe-Zn interactions
• High doses of iron supplements taken together with zinc supplements on
an empty stomach can inhibit the absorption of zinc. When takne with
food, supplemental iron does not appear to inhibit zinc absorption. Ironfortified foods have no effect on zinc absorption. (Textbook)
• When given to adults in solution in ratios of Zn: Iron is >2:1 was found
to compete for absorption with zinc.
(J. Nutr.116:927-935, 1986)
• Divalent metal transporter 1 (DMT1) has an affinity for both Fe and Zn
• Recent studies have shown Zn has a specific transporter, Zn transporter
(ZIN), in the apical membrane and ZIP is the primary transporter of Zn
because Fe disrupt Zn absorption, not vice versa.
(J. Nutr. 134: 1295-1298, 2004, Am J Clin Nutr. 78 (5): 1018, 2003 )
NUTR 650, 10/19/2006
Mineral Interactions
Fe-Mn interactions
• When iron intake was minimal, a small excess of Mn causes
anemia and low serum iron in a lamb.
(Textbook)
• Nonheme iron antagonizes manganese, but not heme iron.
(Am J Clin Nutr. 56:926-932, 1992)
• Absorption of Mn from a meal is reduced as the meal’s iron
content is increased. Intestinal absorption of Mn is increased
during iron deficiency, and increased ferritin levels are
associated with decreased Mn absorption.
NUTR 650, 10/19/2006
Storage Status
•
Iron Deficiency
– Subtle symptoms unless anemia is severe (hemoglobin
<70g/L)
– Mainly three identified (from least to most severe)
 Storage iron depletion
Only iron store is depleted
 Early functional iron deficiency
Iron store is depleted and functional iron is low but not low
enough to cause measurable anemia
 Iron deficiency anemia
Impaired tissue oxygenation, reduced work ability
• Responsible for many maternal death at parturition
Impaired oxidative metabolism in muscle
• shift to gluconeogenesis and lactate utilization
(acidosis)
Behavioral and Intellectual Defects
Body temperature regulation impaired
NUTR 650, 10/19/2006
Deficiency Signs
Glossitis
Koilonychia
“Spoon Nails”
Angular Stomatitis
NUTR 650, 10/19/2006
Storage Status
• Iron Excess & Toxicity
– Acute toxicity - overload transferrin, strong acids
produced by Fe/HCl in stomach kill GI tract
• Bloody vomit and stools
• Systemic effects from conversion of ferrous to
ferric and release of protons
NUTR 650, 10/19/2006
Storage Status
• Iron Excess & Toxicity
– Chronic Iron Toxicity
• Hemosiderosis - excess iron in hemosiderin
• Hemochromotosis - excess iron in fibrotic tissue damage
– common causes = excess ingestion or transfusion
– Genetic hyper absorption - Hemochromatosis
» 3-4/100 of European descent
» Cirrhosis, diabetes, heart failure, arthritis, sexual
dysfunction
» Transferrin saturation good screening test
NUTR 650, 10/19/2006
Thank you
-Arigato
gozaimashitaIron man – Japanese version
NUTR 650, 10/19/2006