Iron metabolism disorders (WP5172)

Homo sapiens

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This pathway was inspired by Figure 40.1 of Chapter 40 (ed. 4) of the book of Blau (ISBN 3642403360 (978-3642403361)). Intestinal iron is reduced by an cytochrome b reductase 1 (CYBRD1) and transported into intestinal cells by the divalent metal transporter SLC11A2 (or DMT1). Inside cells, iron is stored as ferritin (FT). On the basolateral side, iron leaves the epithelium via a basolateral transporter, SLC40A1 (or IREG1), followed by oxidation through the action of hephaestin (Heph), a membrane-bound ceruloplasmin-like multicopper ferroxidase. Iron-loaded transferrin (Fe2-Tf) binds to the transferrin receptor (TfRC) on the surface of cells. The receptor-transferrin complex, localized in clathrin-coated pits (TTTT), is invaginated and forms endosomes. These specialized endosomes acquire a low internal pH due to the action of a proton pump (not shown). This leads to the dissociation of the iron from transferrin. Iron can be converted into its ferrous form by the metalloreductase STEAP3 and then leave the endosomes via SLC11A2. Apo-transferrin and transferrin receptors recycle to the plasma membrane for reuse. This iron uptake mechanism is found in most cell types, including enterocyte precursor cells. Excess iron can leave at least some cell types via SLC40A1 and can be converted to its ferric form by ceruloplasmin (CP), a non-membrane multicopper ferroxidase. Hereditary hemochromatosis results from mutations in HFE. HFE forms a heterodimer with β2-microglobulin, and some mutations that lead to hemochromatosis interrupt this interaction and thus lead to excess iron accumulation. Defects in a second transferrin receptor, TfR2, have recently been implicated in type 3 hemochromatosis. Hepcidin (HAMP) modulates cellular iron export through ferroportin (SLC40A1) by internalizing it into vesicles when the iron concentration is high. HFE, TfR2 and HJV are Hepcidin regulators which are mutated in hereditary hemochromatosis.

Authors

Amaury Pelzer , Emilia Agasi , Denise Slenter , and Eric Weitz

Activity

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Organisms

Homo sapiens

Communities

Inherited Metabolic Disorders (IMD) Pathways

Annotations

Disease Ontology

hyperferritinemia-cataract syndrome hemosiderosis hypochromic microcytic anemia iron metabolism disease mitochondrial complex III deficiency neurodegeneration with brain iron accumulation 3 aceruloplasminemia hemochromatosis type 4 hemochromatosis type 1 pulmonary hemosiderosis hemochromatosis type 5 GRACILE syndrome hemochromatosis type 2B hemochromatosis type 2A hemochromatosis type 3 inherited metabolic disorder immunodeficiency 46 neurodegeneration with brain iron accumulation atransferrinemia

Pathway Ontology

iron uptake pathway altered iron homeostasis pathway regulatory pathway iron homeostasis pathway inborn error of metabolism pathway inborn error of metal metabolism pathway

Cell Type Ontology

enterocyte native cell

Participants
Query Drugst.One

Label Type Compact URI Comment
Fe3+ Metabolite chebi:29034
Fe2+ Metabolite chebi:29033
(R)-4'-phosphopantothenate Metabolite chebi:10986
(R)-pantothenate Metabolite chebi:29032
STEAP3 GeneProduct ensembl:ENSG00000115107
TFR2 GeneProduct ensembl:ENSG00000106327
CP GeneProduct ensembl:ENSG00000047457
FTL GeneProduct ensembl:ENSG00000087086 Ferritin light chain
HJV GeneProduct ensembl:ENSG00000168509
HAMP GeneProduct ensembl:ENSG00000105697
HFE GeneProduct ensembl:ENSG00000010704
SLC11A2 GeneProduct ensembl:ENSG00000110911 This is called 'DMT1' in the book but it is actually SLC11A2 (ENSG00000110911, coding for P49281) as mentioned in the article.
TF GeneProduct ensembl:ENSG00000091513
TFRC GeneProduct ensembl:ENSG00000072274 This is named 'transferrin receptor (TfR)' in the book or TFR1 but the gene name for this protein is TFRC (ENSG00000072274, P02786).
SLC40A1 GeneProduct ensembl:ENSG00000138449 This is called IREG1 the book but it is actually called SLC40A1 (Q9NP59) as mentioned in the article. It is also called FPN1 (ferroportin 1).
HEPH GeneProduct ensembl:ENSG00000089472
CYBRD1 GeneProduct ensembl:ENSG00000071967 This is mentioned in the book as 'an unknown ferric reductase (FR) but it is actually cytochrome b reductase 1 (CYBRD1, ENSG00000071967) as mentioned in the articles linked here.
SLC11A2 GeneProduct ensembl:ENSG00000110911 This is called DMT1 (or NRAMP2) in the book but the correct name is SLC11A2 (ENSG00000110911).
SLC40A1 GeneProduct ensembl:ENSG00000138449
FTH1 GeneProduct ensembl:ENSG00000167996
BCS1L GeneProduct ensembl:ENSG00000074582
PANK2 GeneProduct ensembl:ENSG00000125779
UQCRFS1 GeneProduct ensembl:ENSG00000169021

References

  1. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. Gunshin H, Fujiwara Y, Custodio AO, Direnzo C, Robine S, Andrews NC. J Clin Invest. 2005 May;115(5):1258–66. PubMed Europe PMC Scholia
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  3. The role of hepcidin in iron metabolism. Nemeth E, Ganz T. Acta Haematol. 2009;122(2–3):78–86. PubMed Europe PMC Scholia
  4. Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations. Leoni V, Strittmatter L, Zorzi G, Zibordi F, Dusi S, Garavaglia B, et al. Mol Genet Metab. 2012 Mar;105(3):463–71. PubMed Europe PMC Scholia
  5. HFE gene: Structure, function, mutations, and associated iron abnormalities. Barton JC, Edwards CQ, Acton RT. Gene. 2015 Dec 15;574(2):179–92. PubMed Europe PMC Scholia
  6. A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Jabara HH, Boyden SE, Chou J, Ramesh N, Massaad MJ, Benson H, et al. Nat Genet. 2016 Jan;48(1):74–8. PubMed Europe PMC Scholia
  7. The Regulation of Iron Absorption and Homeostasis. Wallace DF. Clin Biochem Rev. 2016 May;37(2):51–62. PubMed Europe PMC Scholia
  8. Does Ceruloplasmin Defend Against Neurodegenerative Diseases? Wang B, Wang XP. Curr Neuropharmacol. 2019;17(6):539–49. PubMed Europe PMC Scholia
  9. Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis. Gusic M, Schottmann G, Feichtinger RG, Du C, Scholz C, Wagner M, et al. Am J Hum Genet. 2020 Jan 2;106(1):102–11. PubMed Europe PMC Scholia
  10. Idiopathic Pulmonary Hemosiderosis. LaFreniere K, Gupta V. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2022. PubMed Europe PMC Scholia
  11. Cryo-EM structures and functional characterization of homo- and heteropolymers of human ferritin variants. Irimia-Dominguez J, Sun C, Li K, Muhoberac BB, Hallinan GI, Garringer HJ, et al. Sci Rep. 2020 Nov 26;10(1):20666. PubMed Europe PMC Scholia
  12. Down regulation of the expression of mitochondrial phosphopantetheinyl-proteins in pantothenate kinase-associated neurodegeneration: pathophysiological consequences and therapeutic perspectives. Álvarez-Córdoba M, Talaverón-Rey M, Villalón-García I, Povea-Cabello S, Suárez-Rivero JM, Suárez-Carrillo A, et al. Orphanet J Rare Dis. 2021 May 5;16(1):201. PubMed Europe PMC Scholia