Iron metabolism disorders (Homo sapiens)
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Description
This pathway was inspired by Chapter 40 of the book of Blau (ISBN 3642403360 (978-3642403361)).
Pathway of the key elements of iron homeostasis and defects in aceruloplasminemia and hemochromatosis. Intestinal iron is reduced by an cytochrome b reductase 1 (CYBRD1) and transported into intestinal cells by the divalent metal transporter SLC11A2 (or DMT1) and also by other routes. Inside cells, iron is stored as ferritin (FT) and hemosiderin. In erythroid cells, most of the iron moves to mitochondria, where it is incorporated into protoporphyrin to make a heme. 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 (originally called HLA-H), a protein with sequence similarity to major histocompatibility complex class I molecules. 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.
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Saving...Bibliography
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- Jose Irimia-Dominguez, Chen Sun, Kunpeng Li, Barry B Muhoberac, Grace I Hallinan, Holly J Garringer, Bernardino Ghetti, Wen Jiang, Ruben Vidal; ''Cryo-EM structures and functional characterization of homo- and heteropolymers of human ferritin variants''; https://pubmed.ncbi.nlm.nih.gov/33244127/, 2020 PubMed Europe PMC Scholia
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- Blau N, Duran M, Gibson KM, Dionisi-Vici C; ''Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, Chapter 40''; ISBN 978-3-642-40337-8, 2014
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History
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External references
DataNodes
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| Name | Type | Database reference | Comment |
|---|---|---|---|
| CP | GeneProduct | ENSG00000047457 (Ensembl)  | |
| CYBRD1 | GeneProduct | ENSG00000071967 (Ensembl) | 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. |
| Fe2+ | Metabolite | CHEBI:29033 (ChEBI) | |
| Fe3+ | Metabolite | CHEBI:29034 (ChEBI) | |
| HAMP | GeneProduct | ENSG00000105697 (Ensembl) | |
| HEPH | GeneProduct | ENSG00000089472 (Ensembl) | |
| HFE | GeneProduct | ENSG00000010704 (Ensembl) | |
| HJV | GeneProduct | ENSG00000168509 (Ensembl) | |
| SLC11A2 | GeneProduct | ENSG00000110911 (Ensembl) | This is called DMT1 (or NRAMP2) in the book but the correct name is SLC11A2 (ENSG00000110911). |
| SLC40A1 | GeneProduct | ENSG00000138449 (Ensembl) | 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). |
| STEAP3 | GeneProduct | ENSG00000115107 (Ensembl) | |
| TF | GeneProduct | ENSG00000091513 (Ensembl) | |
| TFR2 | GeneProduct | ENSG00000106327 (Ensembl) | |
| TFRC | GeneProduct | ENSG00000072274 (Ensembl) | This is named "transferrin receptor (TfR)" in the book or TFR1 but the gene name for this protein is TFRC (ENSG00000072274, P02786). |
Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| Arrow | R-HSA-917807.2 (Reactome) | |||
| Fe2+ | Fe2+ | Arrow | 28487 (Rhea) | |
| Fe2+ | Fe2+ | Arrow | 29581 (Rhea) | |
| Fe2+ | Fe3+ | mim-conversion | 11149 (Rhea) | |
| Fe2+ | Fe3+ | mim-conversion | 28487 (Rhea) | |
| Fe3+ | Fe2+ | mim-conversion | R-HSA-917805.3 (Reactome) | |
| Fe3+ | Fe2+ | mim-conversion | R-HSA-917811.1 (Reactome) | |
| Fe3+ | mim-modification | R-HSA-917835.1 (Reactome) | ||
| HEPH | mim-catalysis | R-HSA-917933.2 (Reactome) | ||
| TF | mim-binding | R-HSA-917888.2 (Reactome) | ||
| mim-binding | R-HSA-917987.1 (Reactome) | |||
| mim-modification | R-HSA-917835.1 (Reactome) |
