10/19/2006Yuka Mitsuhashi

-Scandinavian “Iarn"

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+

NUTR 650, 10/19/2006

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

NUTR 650, 10/19/2006

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

Mn

Fe

CuZn (-) (+)

(-)

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

NUTR 650, 10/19/2006

• 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

NUTR 650, 10/19/2006

Thank you Thank you -Arigato-Arigato

gozaimashita-gozaimashita-

Iron man – Japanese version