1 / 86

Iron metabolism

Iron metabolism. Dr Artur Słomka Department of Pathophysiology Collegium Medicum in Bydgoszcz Poland. Košice , April 2016. Iron at a glance. Human iron physiology. 3 mg of Fe. Int J Hematol. 2011;93(1):14-20. Human iron physiology. Henry John Horstman Fenton

wayala
Download Presentation

Iron metabolism

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Iron metabolism Dr Artur Słomka 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. 2011;93(1):14-20

  4. Human iron physiology

  5. Henry John Horstman Fenton Oxidation of tartaric acid in presence of iron. J. Chem. Soc., Trans. 1894;65, 899-910 hydroxylradical DNA, proteins, lipids, carbohydrates Cellular injury

  6. Iron forms Fe2+ Fe3+

  7. Fourgeneralcategoriesof iron-containingproteins Iron-containingnonenzymaticproteins Heme-containingenzymes Iron-sulfurenzymes Nonheme proteins

  8. List of selected eukaryotic hemoproteins Electron transport Gas binding Transcriptionfactors Theremainingmetabolicprocesses Front Pharmacol. 2014;5:126

  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 thelungs to the tissues. • Mioglobin • the single-chain hemoprotein in muscletissues, • the concentration of myoglobin in skeletal muscle is drastically reduced (40–60%) in tissue iron deficiency. Iron-containingnonenzymaticproteins

  10. Four general categories of iron-containing proteins In 1862, Felix Seyleridentifiedthe respiratory protein hemoglobin. 26 December 1825 – 10 August 1895

  11. Four general categories of iron-containing proteins In 1962, Max Perutztogetherwith Sir John CowderyKendrew (1917-1997) receivedthe 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.org. Nobel Media AB 2014. Web. 1 Apr 2015. <http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1962/> Blood2008;112:3927-38

  12. Fourgeneralcategoriesof iron-containingproteins Myoglobin was the first proteindescribed by X-raycrystallography. (Nature1958 ;181:662-6) Sir John Cowdery Kendrew, CBE 24 March 1917 – 23 August 1997 J Mol Biol. 2009;392:2–32

  13. Fourgeneralcategoriesof iron-containingproteins • NADH–coenzyme Q reductase, succinate–coenzyme Q reductase and Rieskeproteins • electron transport chain. • Mitochondrialaconitase • Krebs cycle (TCA cycle). • Ribonucleotidereductase • synthesis of DNA. Iron-sulfurenzymes

  14. Fourgeneralcategoriesof iron-containingproteins • Cytochromes • P–450, A, A3, B and C - electron transport. • Catalase • decompositionof  H2O2 to water and oxygen. Heme-containingenzymes

  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 inthebrain 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. 2000;48(2):169-76

  18. Myelinogenesis Cerebellar whitematter 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. 1986;125(3):620-4

  19. Iron and brain functions • myelinogenesis: • iron deficiency  reductionof myelination in the spinalcord (↓ nervonicacid). • functions of neurons: • iron deficiency • reduction of cytochrome c oxidase (CytOx) activity   ↓ memoryprocesses, • ↓ gamma-aminobutyricacid and ↓ glutamate (withoutaffecting hemoglobin), • ↓ dopamine D2 receptor, • ↓ 5-hydroxytryptamine (serotonin).

  20.  Source of iron • diet is the only source of iron forhumans, • the normal diet should contain 13–18 mg of iron per day, • only1 mg of dietary iron is absorbed (even in ID absorption is only 2–4 mg), • two forms of dietary iron: heme (∼15% of iron in regular diet) and nonheme (∼85% of iron in regular diet), • heme iron - mostlyfromanimal products (red meat), • nonheme (inorganic) iron - mostlyfrom plant foods.

  21.  Source of iron Dietary iron

  22. Regulation of cellular iron metabolism • proteins involve in iron metabolism areregulated bythe 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.

  23. IRPs ↓ Iron ↑Iron IRPs bind to 5’ IREs inferritin and ferroportinmRNAs to represstranslation, and to 3’ IREs in TfR1mRNA to block its degradation. IRPs do notbind to IREs,increasing synthesis of ferritin and ferroportin, whilepromoting the degradation of TfR1 mRNA.

  24. Ferritin Ferritin was discovered in 1937 by V. Laufberger. (Sur la cristallisation de la ferritine. Bulletin de la Societe de chimie biologique.1937;19:1575–1582) Ferritin molecule H chain ferritin Biochim Biophys Acta. 2010;1800(8):706-18

  25. ferroxidaseactivity (Fe2+Fe3+) serum ferrritin

  26.  Ferritin ↑ H ↑ L • TNFα, • interleukins:1 and 6,  • interferon-γ. • iron, • prostaglandins. ↑ H and ↑ L • TRH and T3,  • insulin and IGF-1, • oxidants.

  27.  Ferritin and glucose Effect of glucose on ferritin in culturedpancreatic islets. Islets were maintained for 24 h in tissue culturemedium containing either 1 mM glucose or 20 mM glucose. FASEB J. 1994;8(10):777-81

  28.  Ferritin • the major function of ferritin is to limit Fe(II) available to participate in the generation of ROS, • serum ferritin isdirectly related to intracellular ferritin. • CLINICAL UTYLITY • test for diagnosing ID (≤15μg/L), • an acute-phase protein  patients with inflammatorydisorders/liverdiseasemayhavenormalorincreased ferritin.

  29. Lancet. 2015

  30. Serum ferritin - cutoffs Lancet. 2015

  31.  Ferritin in human disease Int J Inflam. 2012;2012:298405

  32.  Ferritin in human disease Rheumatology (Oxford). 2002;41(2):216-22/Ther Clin Risk Manag. 2014;11:33-43

  33.  Ferritin in human disease Fe2+ L-DOPA Ther Clin Risk Manag. 2006;2(4):465-75

  34. Transferrins • nonhemeiron-bindingglycoproteins, • 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).

  35. Holo-form of serum Tf Apo-form of serum Tf Biochim Biophys Acta. 2012;1820(3):417-26

  36.  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.

  37.  Transferrin receptor 1 (CD71) Pharmacol Rev. 2002;54(4):561-87

  38.  Transferrin receptor 1 • can bind up to two molecules of transferrin, • expressed in all nucleated cells (mostly on proliferatingcells), • binds two proteins critical for iron metabolism:transferrin andHFE (humanhemochromatosis). It has been demonstrated that targeting of transferrin receptor is effective in deliveringtherapeutic agents to cancer cells.

  39. J Cell Biol. 2003;162(5):909-18  Tf cycle (∼2-3 minutes) • Zip14 • TRPML1 Biochim Biophys Acta. 2012;1820(3):326-33 Nat Genet. 2005;37(11):1264-9

  40.  HFE β2-microglobulin

  41.  Transferrin receptor 2

  42. Soluble transferrin receptor

  43. Changes in sTfR concentration Am J Hematol. 2008;83(11):872-5

  44. DMT1/ DCT1/Slc11a2/ Nramp2

  45. DMT1/ DCT1/Slc11a2/ Nramp2 Blood morphology of wild type mice. Blood morphology of Slc11a2–/– mice. J Clin Invest. 2005;115(5):1258-66

  46. HEPCIDINThe milestone in iron metabolism

  47. Discovery of hepcidin

  48. hepatocyte microbicidal activity

More Related