10/19/2006 yuka mitsuhashi -scandinavian “iarn". nutr 650, 10/19/2006 1.history 2.fact -...
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NUTR 650, 10/19/2006
1. History2. Fact - chemistry3. Function4. Distribution5. Functional and storage iron6. Absorption7. Homeostasis8. Fe - mineral interaction9. Storage Status
OverviewOverview
NUTR 650, 10/19/2006
• 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
HistorHistoryy
NUTR 650, 10/19/2006
• 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
HistorHistoryy
NUTR 650, 10/19/2006
• 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-
FactsFacts
NUTR 650, 10/19/2006
Flavoproteins
Hemeproteins
Fe-sulfurNzms
Other FeNzms
Other FeProteins
Fe-Containing
Proteins
Transferrin&
Others
Ferritin&
Hemosiderin
Other NzmsHemeFlavoproteins
Hemoglobin
Other Nzms
IronActivated
Nzms
2Fe-2S4Fe-4SNzms
Myoglobin Cytochromes Other Nzms
FunctionFunction
NUTR 650, 10/19/2006
FunctionFunction• 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
DistributiDistributiononCompoun
dMale
(mg/kg)Female (mg/kg)
Functional
Hemoglobin 31 26
Myoglobin 4 3Heme Nzm 1 1Nonheme Nzm 1 1Transferrin Iron 0.05 0.05
Total 37 (74%) 33 (87%)Storage Ferritin 9 4
Hemosiderin 4 1Total 13 (26%) 5 (13%)
Body Total mg/kg
50 38
Handbook of Nutritionally Essential Mineral Elements
NUTR 650, 10/19/2006
DistributiDistributionon
Iron
Req
uir
em
en
t m
g/d
ay
6
5
4
3
2
1Body Iron Loss
Fetus
Menstruation
Menstruation
LactationRed Cells
Non gravid 1st 2nd 3rd
Trimester
Postpartum
NUTR 650, 10/19/2006
Whole body fluxesWhole body fluxes
Hemoglobin(~2500mg)
Plasma Iron (transferrin)
Iron Intake (10-14mg→0.5-2mg)
Stores(1500mg)
Myoglobin (200mg)Enzyme Iron (5mg)
Iron Loss (1-2mg)
Ferritin Hemosiderin
Liver, SpleenBone marrow
Erythrocyte
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Functional Functional ironiron
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 IronStorage 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 IronStorage Iron
Hemosiderin• ~50% liver iron stores• Reacts to ferritin antibodies - likely a
degradation product• Insoluble, ~30% iron by weight• Less available for mobilization
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Iron forms in Iron forms in dietsdiets• 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+
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AbsorptionAbsorption
Nonheme
1. Iron solublized and ionized by stomach acid2. Chelation with small molecularweight compounds and mucin
3. Iron chelates pass throughunstirred water layer bind to surface proteins and are internalized
4. Absorption all along the small intestine, but highest in duodenum
Heme
1. Protein digestion of hemoglobin and myoglobin releases heme
2. Heme transported as such into the cell
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AbsorptioAbsorptionn
• Ferrous, Fe2+, most soluble = most absorbable
• Each mechanism has 3 phases– Iron uptake– Intraenterocyte transport– Storage and extraenterocyte transfer
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AbsorptionAbsorptionDuodenal Lumen Duodenal Mucosa Plasma
B2-microglobulin
HFE
DMT1
B3 integrin
MucinFe++
Fe++ Fe++
FeFe2+2+
FeFe33
++
Mobilferritin
Heme-Protein
Heme+
Polypeptides
Heme
Biliverdin Bilirubin Bilirubin
Heme
OxigenaseCO CO
paraferritinFeFe2+2+ FeFe2+2+
FeFe33
++Transferritin
Ceruloplasmin
Ferroportin
NUTR 650, 10/19/2006
AbsorptioAbsorptionn
Factors affecting Iron Absorption– 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%
Iron uptake - Duodenal lumen to Duodenal mucosa
NUTR 650, 10/19/2006
AbsorptionAbsorption
• Promotors– Amino Acids– Animal Proteins(for
heme)– Ascorbic Acid– Hydrochloric Acid– Organic Acids– Sugars– Mucin
• Inhibitors– Carbonates– Calcium (for heme)– Egg yolk phosvitin– Fiber– Oxalates– Phosphates– Phytates– Plant polyphenols– Soy proteins
Iron uptake phase - Duodenal lumen to Duodenal mucosa
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Transferrin Transferrin ReceptorReceptor
• 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
Storage and extraenterocyte transfer phase
NUTR 650, 10/19/2006
Intracellular iron metabolismIntracellular iron metabolism and homeostasisand homeostasis
Handbook of Nutritionally Essential Mineral Elements
NUTR 650, 10/19/2006
HomeostasisHomeostasis
Low IronHigh IronIron-ResponsiveElement(IRE) bound by IRP?
Yes NO
Ferritin mRNAtranslation
FerritinSynthesis
RepressedActivated
TfR mRNAstability
TfRsynthesis
IncreasedDecreased
5’ AAAn
3’
Ferritin mRNA
Transferrin Receptor(TfR) mRNA
5’ AAAn
3’
•Iron Regulatory Proteins - Regulate iron storage and metabolism
- Bind to iron response elements and regulate the synthesis of specific proteins
NUTR 650, 10/19/2006
Mineral InteractionsMineral 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)
Fe-Cu interactions
NUTR 650, 10/19/2006
Mineral InteractionsMineral 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. Iron-fortified 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 )
Fe-Zn interactions
NUTR 650, 10/19/2006
Mineral InteractionsMineral 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.
Fe-Mn interactions
NUTR 650, 10/19/2006
• 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 anemiaImpaired tissue oxygenation, reduced work ability• Responsible for many maternal death at parturitionImpaired oxidative metabolism in muscle• shift to gluconeogenesis and lactate utilization (acidosis)Behavioral and Intellectual DefectsBody temperature regulation impaired
Storage Storage StatusStatus
NUTR 650, 10/19/2006
Deficiency Deficiency SignsSigns
Koilonychia“Spoon Nails”
Glossitis
Angular Stomatitis
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• 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
Storage Storage StatusStatus
NUTR 650, 10/19/2006
• 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
Storage Storage StatusStatus