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IRON

IRON. -Scandinavian “Iarn". 10/19/2006 Yuka Mitsuhashi. Overview. History Fact - chemistry Function Distribution Functional and storage iron Absorption Homeostasis Fe - mineral interaction Storage Status. History.

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IRON

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  1. IRON -Scandinavian “Iarn" 10/19/2006 Yuka Mitsuhashi

  2. Overview • History • Fact - chemistry • Function • Distribution • Functional and storage iron • Absorption • Homeostasis • Fe - mineral interaction • Storage Status

  3. 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

  4. 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

  5. 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-

  6. Heme Flavoproteins 2Fe-2S 4Fe-4S Nzms Flavoproteins Other Nzms Iron Activated Nzms Transferrin & Others Ferritin & Hemosiderin Other Nzms Cytochromes Other Nzms Hemoglobin Myoglobin Function Fe-sulfur Nzms Other Fe Proteins Other Fe Nzms Fe-Containing Proteins Hemeproteins

  7. 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

  8. Distribution Handbook of Nutritionally Essential Mineral Elements

  9. Distribution 6 5 4 3 2 1 Fetus Iron Requirement mg/day Menstruation Lactation Red Cells Menstruation Body Iron Loss 1st 2nd 3rd Non gravid Postpartum Trimester

  10. Whole body fluxes Iron Intake (10-14mg→0.5-2mg) Plasma Iron (transferrin) Myoglobin (200mg) Enzyme Iron (5mg) Erythrocyte Liver, Spleen Bone marrow Hemoglobin (~2500mg) Ferritin Hemosiderin Stores (1500mg) Iron Loss (1-2mg)

  11. 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

  12. 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

  13. Storage Iron Hemosiderin • ~50% liver iron stores • Reacts to ferritin antibodies - likely a degradation product • Insoluble, ~30% iron by weight • Less available for mobilization

  14. 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+

  15. Heme 1. Iron solublized and ionized by stomach acid 1. Protein digestion of hemoglobin and myoglobin releases heme 2. Chelation with small molecular weight compounds and mucin 3. Iron chelates pass through unstirred water layer bind to surface proteins and are internalized 2. Heme transported as such into the cell 4. Absorption all along the small intestine, but highest in duodenum Absorption Nonheme

  16. Absorption • Ferrous, Fe2+, most soluble = most absorbable • Each mechanism has 3 phases • Iron uptake • Intraenterocyte transport • Storage and extraenterocyte transfer

  17. Heme- Protein Heme + Polypeptides Biliverdin Bilirubin Bilirubin CO CO Heme Oxigenase B2-microglobulin Heme Fe2+ Fe2+ Fe3+ paraferritin Fe++ Fe++ Ceruloplasmin Fe++ Fe2+ Mucin Fe3+ Mobilferritin Transferritin Absorption Duodenal Lumen Duodenal Mucosa Plasma HFE Ferroportin DMT1 B3 integrin

  18. Absorption Iron uptake - Duodenal lumen to Duodenal mucosa 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%

  19. 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 Absorption Iron uptake phase - Duodenal lumen to Duodenal mucosa

  20. 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

  21. Intracellular iron metabolism　and homeostasis Handbook of Nutritionally Essential Mineral Elements

  22. Low Iron High Iron Iron-Responsive Yes NO Element(IRE) bound by IRP? Repressed Activated Ferritin mRNA translation 3’ Ferritin Ferritin mRNA AAAn 5’ Synthesis Increased Decreased TfR mRNA stability 3’ Transferrin Receptor (TfR) mRNA TfR AAAn 5’ synthesis Homeostasis • Iron Regulatory Proteins • - Regulate iron storage and metabolism • - Bind to iron response elements and regulate the synthesis of specific proteins

  23. (-) (+) Mineral Interactions Cu Zn Fe (-) Mn

  24. 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 ratsand 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)

  25. 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. 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 )

  26. 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.

  27. 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

  28. Deficiency Signs Glossitis Koilonychia “Spoon Nails” Angular Stomatitis

  29. 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

  30. 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

  31. Thank you -Arigatogozaimashita- Iron man – Japanese version

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