The transport of iron between cells is mediated by transferrin. However, iron can also enter and leave cells not only by itself, but also in the form of heme and siderophores. When entering the cell via the main path (by transferrin endocytosis), its goal is not the (still elusive) chelated iron pool in the cytosol nor the lysosomes but the mitochondria, where heme is synthesized and iron-sulfur clusters are assembled (Kurz et al,2008, Hower et al 2009, Richardson et al 2010).
View original pathway at Reactome.
Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, Akira S, Aderem A.; ''Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron.''; PubMedEurope PMCScholia
Harrison PM, Arosio P.; ''The ferritins: molecular properties, iron storage function and cellular regulation.''; PubMedEurope PMCScholia
Trinder D, Baker E.; ''Transferrin receptor 2: a new molecule in iron metabolism.''; PubMedEurope PMCScholia
Samaniego F, Chin J, Iwai K, Rouault TA, Klausner RD.; ''Molecular characterization of a second iron-responsive element binding protein, iron regulatory protein 2. Structure, function, and post-translational regulation.''; PubMedEurope PMCScholia
Kawabata H, Yang R, Hirama T, Vuong PT, Kawano S, Gombart AF, Koeffler HP.; ''Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family.''; PubMedEurope PMCScholia
Salahudeen AA, Thompson JW, Ruiz JC, Ma HW, Kinch LN, Li Q, Grishin NV, Bruick RK.; ''An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis.''; PubMedEurope PMCScholia
Camaschella C, Roetto A, Calì A, De Gobbi M, Garozzo G, Carella M, Majorano N, Totaro A, Gasparini P.; ''The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22.''; PubMedEurope PMCScholia
Levi S, Corsi B, Bosisio M, Invernizzi R, Volz A, Sanford D, Arosio P, Drysdale J.; ''A human mitochondrial ferritin encoded by an intronless gene.''; PubMedEurope PMCScholia
Langlois d'Estaintot B, Santambrogio P, Granier T, Gallois B, Chevalier JM, Précigoux G, Levi S, Arosio P.; ''Crystal structure and biochemical properties of the human mitochondrial ferritin and its mutant Ser144Ala.''; PubMedEurope PMCScholia
Griffiths TA, Mauk AG, MacGillivray RT.; ''Recombinant expression and functional characterization of human hephaestin: a multicopper oxidase with ferroxidase activity.''; PubMedEurope PMCScholia
Supek F, Supekova L, Mandiyan S, Pan YC, Nelson H, Nelson N.; ''A novel accessory subunit for vacuolar H(+)-ATPase from chromaffin granules.''; PubMedEurope PMCScholia
Dupuy J, Volbeda A, Carpentier P, Darnault C, Moulis JM, Fontecilla-Camps JC.; ''Crystal structure of human iron regulatory protein 1 as cytosolic aconitase.''; PubMedEurope PMCScholia
Rey MA, Duffy SP, Brown JK, Kennedy JA, Dick JE, Dror Y, Tailor CS.; ''Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis.''; PubMedEurope PMCScholia
West AP, Giannetti AM, Herr AB, Bennett MJ, Nangiana JS, Pierce JR, Weiner LP, Snow PM, Bjorkman PJ.; ''Mutational analysis of the transferrin receptor reveals overlapping HFE and transferrin binding sites.''; PubMedEurope PMCScholia
Dong XP, Cheng X, Mills E, Delling M, Wang F, Kurz T, Xu H.; ''The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel.''; PubMedEurope PMCScholia
Zheng J, Yang X, Harrell JM, Ryzhikov S, Shim EH, Lykke-Andersen K, Wei N, Sun H, Kobayashi R, Zhang H.; ''CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex.''; PubMedEurope PMCScholia
Richardson DR, Lane DJ, Becker EM, Huang ML, Whitnall M, Suryo Rahmanto Y, Sheftel AD, Ponka P.; ''Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol.''; PubMedEurope PMCScholia
Wakabayashi K, Nakagawa H, Tamura A, Koshiba S, Hoshijima K, Komada M, Ishikawa T.; ''Intramolecular disulfide bond is a critical check point determining degradative fates of ATP-binding cassette (ABC) transporter ABCG2 protein.''; PubMedEurope PMCScholia
Devireddy LR, Hart DO, Goetz DH, Green MR.; ''A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production.''; PubMedEurope PMCScholia
Oakhill JS, Marritt SJ, Gareta EG, Cammack R, McKie AT.; ''Functional characterization of human duodenal cytochrome b (Cybrd1): Redox properties in relation to iron and ascorbate metabolism.''; PubMedEurope PMCScholia
Ohgami RS, Campagna DR, McDonald A, Fleming MD.; ''The Steap proteins are metalloreductases.''; PubMedEurope PMCScholia
Goetz DH, Holmes MA, Borregaard N, Bluhm ME, Raymond KN, Strong RK.; ''The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition.''; PubMedEurope PMCScholia
Sato M, Schilsky ML, Stockert RJ, Morell AG, Sternlieb I.; ''Detection of multiple forms of human ceruloplasmin. A novel Mr 200,000 form.''; PubMedEurope PMCScholia
Harding C, Heuser J, Stahl P.; ''Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes.''; PubMedEurope PMCScholia
Willingham MC, Hanover JA, Dickson RB, Pastan I.; ''Morphologic characterization of the pathway of transferrin endocytosis and recycling in human KB cells.''; PubMedEurope PMCScholia
Philpott CC, Klausner RD, Rouault TA.; ''The bifunctional iron-responsive element binding protein/cytosolic aconitase: the role of active-site residues in ligand binding and regulation.''; PubMedEurope PMCScholia
Haunhorst P, Hanschmann EM, Bräutigam L, Stehling O, Hoffmann B, Mühlenhoff U, Lill R, Berndt C, Lillig CH.; ''Crucial function of vertebrate glutaredoxin 3 (PICOT) in iron homeostasis and hemoglobin maturation.''; PubMedEurope PMCScholia
Tandy S, Williams M, Leggett A, Lopez-Jimenez M, Dedes M, Ramesh B, Srai SK, Sharp P.; ''Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco-2 cells.''; PubMedEurope PMCScholia
Han O, Kim EY.; ''Colocalization of ferroportin-1 with hephaestin on the basolateral membrane of human intestinal absorptive cells.''; PubMedEurope PMCScholia
Kaptain S, Downey WE, Tang C, Philpott C, Haile D, Orloff DG, Harford JB, Rouault TA, Klausner RD.; ''A regulated RNA binding protein also possesses aconitase activity.''; PubMedEurope PMCScholia
Goldenberg SJ, Cascio TC, Shumway SD, Garbutt KC, Liu J, Xiong Y, Zheng N.; ''Structure of the Cand1-Cul1-Roc1 complex reveals regulatory mechanisms for the assembly of the multisubunit cullin-dependent ubiquitin ligases.''; PubMedEurope PMCScholia
Turi JL, Wang X, McKie AT, Nozik-Grayck E, Mamo LB, Crissman K, Piantadosi CA, Ghio AJ.; ''Duodenal cytochrome b: a novel ferrireductase in airway epithelial cells.''; PubMedEurope PMCScholia
Zhang W, Mojsilovic-Petrovic J, Andrade MF, Zhang H, Ball M, Stanimirovic DB.; ''The expression and functional characterization of ABCG2 in brain endothelial cells and vessels.''; PubMedEurope PMCScholia
Kurz T, Terman A, Gustafsson B, Brunk UT.; ''Lysosomes in iron metabolism, ageing and apoptosis.''; PubMedEurope PMCScholia
Vashisht AA, Zumbrennen KB, Huang X, Powers DN, Durazo A, Sun D, Bhaskaran N, Persson A, Uhlen M, Sangfelt O, Spruck C, Leibold EA, Wohlschlegel JA.; ''Control of iron homeostasis by an iron-regulated ubiquitin ligase.''; PubMedEurope PMCScholia
Wally J, Halbrooks PJ, Vonrhein C, Rould MA, Everse SJ, Mason AB, Buchanan SK.; ''The crystal structure of iron-free human serum transferrin provides insight into inter-lobe communication and receptor binding.''; PubMedEurope PMCScholia
Qin A, Cheng TS, Lin Z, Pavlos NJ, Jiang Q, Xu J, Dai KR, Zheng MH.; ''Versatile roles of V-ATPases accessory subunit Ac45 in osteoclast formation and function.''; PubMedEurope PMCScholia
Devireddy LR, Gazin C, Zhu X, Green MR.; ''A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake.''; PubMedEurope PMCScholia
Xu J, Liu Y, Yang Y, Bates S, Zhang JT.; ''Characterization of oligomeric human half-ABC transporter ATP-binding cassette G2.''; PubMedEurope PMCScholia
Chen H, Attieh ZK, Dang T, Huang G, van der Hee RM, Vulpe C.; ''Decreased hephaestin expression and activity leads to decreased iron efflux from differentiated Caco2 cells.''; PubMedEurope PMCScholia
Shayeghi M, Latunde-Dada GO, Oakhill JS, Laftah AH, Takeuchi K, Halliday N, Khan Y, Warley A, McCann FE, Hider RC, Frazer DM, Anderson GJ, Vulpe CD, Simpson RJ, McKie AT.; ''Identification of an intestinal heme transporter.''; PubMedEurope PMCScholia
Hower V, Mendes P, Torti FM, Laubenbacher R, Akman S, Shulaev V, Torti SV.; ''A general map of iron metabolism and tissue-specific subnetworks.''; PubMedEurope PMCScholia
Hémadi M, Ha-Duong NT, El Hage Chahine JM.; ''The mechanism of iron release from the transferrin-receptor 1 adduct.''; PubMedEurope PMCScholia
Doyle L, Ross DD.; ''Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2).''; PubMedEurope PMCScholia
Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, Sharp JJ, Fujiwara Y, Barker JE, Fleming MD.; ''Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells.''; PubMedEurope PMCScholia
Hori T, Osaka F, Chiba T, Miyamoto C, Okabayashi K, Shimbara N, Kato S, Tanaka K.; ''Covalent modification of all members of human cullin family proteins by NEDD8.''; PubMedEurope PMCScholia
Adachi K, Oiwa K, Nishizaka T, Furuike S, Noji H, Itoh H, Yoshida M, Kinosita K.; ''Coupling of rotation and catalysis in F(1)-ATPase revealed by single-molecule imaging and manipulation.''; PubMedEurope PMCScholia
Schimanski LM, Drakesmith H, Merryweather-Clarke AT, Viprakasit V, Edwards JP, Sweetland E, Bastin JM, Cowley D, Chinthammitr Y, Robson KJ, Townsend AR.; ''In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations.''; PubMedEurope PMCScholia
Feder JN, Penny DM, Irrinki A, Lee VK, Lebrón JA, Watson N, Tsuchihashi Z, Sigal E, Bjorkman PJ, Schatzman RC.; ''The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.''; PubMedEurope PMCScholia
Quigley JG, Yang Z, Worthington MT, Phillips JD, Sabo KM, Sabath DE, Berg CL, Sassa S, Wood BL, Abkowitz JL.; ''Identification of a human heme exporter that is essential for erythropoiesis.''; PubMedEurope PMCScholia
The ferritin complex is an oligomer of 24 subunits with light and heavy chains. The structural features of ferritin arise from the combination in various ratios of two subunits, H and L, which differ in size, amino acid composition, surface charge, and immunoreactivity. A corollary related differences in ferritin iron content to the functional efficiency of one of the two subunits for storing iron. In humans the H subunit is associated with a lower pI and lower iron content, and predominates in heart tissue, whereas the L subunit is associated with a higher pI and higher iron content, and predominates in the liver.
The functional molecule forms a roughly spherical shell with a diameter of 12 nm and contains a central cavity into which the insoluble mineral iron core is deposited. Iron metabolism provides a useful example of gene expression translational control. Increased iron levels stimulate the synthesis of the iron-binding protein, ferritin, without any corresponding increase in the amount of ferritin mRNA. The 5'-UTR of both ferritin heavy chain mRNA and light chain mRNA contain a single iron-response element (IRE), a specific cis-acting regulatory sequence which forms a hairpin structure.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
Ferritin oxidises Fe(2+) ions to Fe(3+), migrates them to its centre, and collects thousands of them as ferric hydroxide (Fe(3+)O(OH)) in the central mineral core from which they can be later remobilised (Harrison & Arrosio 1996).
Heme oxygenase (HO) cleaves the heme ring at the alpha-methene bridge to form bilverdin. This reaction forms the only endogenous source of carbon monoxide. HO-1 is inducible and is thought to have an antioxidant role as it's activated in virtually all cell types and by many types of "oxidative stress" (Poss and Tonegawa, 1997). HO-2 is non-inducible.
The primary site for absorption of dietary iron is the duodenum. Ferrous iron (Fe2+) is taken up from the gut lumen across the apical membranes of enterocytes and released into the portal vein circulation across basolateral membranes. The human gene SLC11A2 encodes the divalent cation transporter DCT1 (NRAMP2, Natural resistance-associated macrophage protein 2). DCT1 resides on the apical membrane of enterocytes and mediates the uptake of many metal ions, particularly ferrous iron, into these cells (Tandy et al. 2000).
The primary site for absorption of dietary iron is the duodenum. Ferrous iron (Fe2+) is taken up from the gut lumen across the apical membranes of enterocytes and released into the portal vein circulation across basolateral membranes. The human gene SLC40A1 encodes the metal transporter protein MTP1 (aka ferroportin or IREG1). This protein resides on the basolateral membrane of enterocytes and mediates ferrous iron efflux into the portal vein (Schimanski et al. 2005). MTP1 colocalizes with hephaestin (HEPH) which stablizes MTP1 and is necessary for the efflux reaction to occur (Han & Kim 2007, Chen et al. 2009). As well as the dudenum, MTP1 is also highly expressed on macrophages (where it mediates iron efflux from the breakdown of haem) and the placenta (where it may mediate the transport of iron from maternal to foetal circulation). It is also expressed in muscle and spleen.
Neutrophil gelatinase associated lipocalin (LCN2, NGAL) is a member of the lipocalin superfamily that is involved in iron trafficking both in and out of cells. LCN2 binds iron via an association with 2,5 dihydroxybenzoic acid (2,5DHBA), a siderophore that shares structural similarities with bacterial enterobactin, and delivers or removes iron from the cell via interacting with different receptors, depending on cellular requirement (Goetz et al. 2002, Devireddy et al. 2010). LCN2 is a potent bacteriostatic agent in iron limiting conditions therefore it is proposed that LCN2 participates in the antibacterial iron depletion strategy of the innate immune system (Flo et al. 2004).
Neutrophil gelatinase-associated lipocalin (LCN2, NGAL) is a member of the lipocalin superfamily that is involved in iron trafficking both in and out of cells (Goetz et al. 2002). LCN2 binds iron through association with 2,5-dihydroxybenzoic acid (2,5DHBA), a siderophore that shares structural similarities with bacterial enterobactin, and delivers or removes iron from the cell, depending on the context. The iron-bound form of LCN2 (holo-LCN2) is internalised following binding to the solute carrier family 22 member 17 (SLC22A17) receptor, leading to release of iron which increases intracellular iron concentration and subsequent inhibition of apoptosis. This step is inferred from experiments using the highly homologous 24p3 mouse lipocalin and 24p3R mouse cell surface receptor (Devireddy et al. 2005). During infection, bacteria scavenge iron from the host cell and transfer it to the pathogen cell. Upon encountering invading bacteria, Toll-like receptors on immune cells can stimulate the transcription, translation and secretion of LCN2. LCN2 can then limit bacterial growth by sequestrating the iron-laden siderophore so this event is pivotal in the innate immune response to bacterial infection (Flo et al. 2004).
Vacuolar-type H+-ATPases (V-ATPases) are proton pumps that acidify intracellular cargos and deliver protons across the plasma membrane of many specialised cells. V-type proton ATPase subunit S1 (ATP6AP1) is thought to function as an accessory subunit of the V0 subcomplex of V-ATPase, facilitating acidification (Supek et al. 1994). Experiments with the mouse orthologue reveals a role for Atp6ap1 in osteoclast formation and function (Qin et al. 2011).
Neutrophil gelatinase-associated lipocalin (LCN2, NGAL) is a member of the lipocalin superfamily that is involved in iron trafficking both in and out of cells (Goetz et al. 2002). LCN2 binds iron through association with 2,5-dihydroxybenzoic acid (2,5DHBA), a siderophore that shares structural similarities with bacterial enterobactin, and delivers or removes iron from the cell, depending on the context. The iron-bound form of LCN2 (holo-LCN2) is internalised following binding to the solute carrier family 22 member 17 (SLC22A17) receptor, leading to release of iron which increases intracellular iron concentration and subsequent inhibition of apoptosis. This step is inferred from experiments using the highly homologous 24p3 mouse lipocalin and 24p3R mouse cell surface receptor (Devireddy et al. 2005).
Iron and citrate are essential for the metabolism of most organisms so their regulation is critical for normal physiology and survival. Depending on cellular conditions, cytoplasmic aconitate hydratase (ACO1 aka iron regulatory protein 1, IRP1) can assume two different functions. During iron scarcity or oxidative stress, ACO1 functions as IRP1, binding to iron responsive elements (IREs) to modulate the translation of iron metabolism genes. In iron-rich conditions, IRP1 binds an iron-sulfur cluster (4Fe-4S) to function as a cytosolic aconitase. This functional duality of IRP1 connects the translational control of iron metabolising proteins to cellular iron levels.
Under iron-replete conditions, ACO1 binds the cofactor 4Fe-4S cluster and acts as an aconitase, isomerising citrate (CIT) to isocitrate (ISCIT) (Kaptain et al. 1991, Philpott et al. 1994, Dupuy et al. 2006).
Iron and citrate are essential for the metabolism of most organisms so their regulation is critical for normal physiology and survival. Depending on cellular conditions, cytoplasmic aconitate hydratase (ACO1 aka iron regulatory protein 1, IRP1) can assume two different functions. During iron scarcity or oxidative stress, ACO1 functions as IRP1, binding to iron responsive elements (IREs) to modulate the translation of iron metabolism genes. In iron-rich conditions, IRP1 binds an iron-sulfur cluster (4Fe-4S) to function as a cytosolic aconitase. This functional duality of IRP1 connects the translational control of iron metabolising proteins to cellular iron levels.
During iron scarcity, ACO1 and iron-responsive element-binding protein 2 (IREB2) bind with high affinity to RNA stem-loops known as iron-responsive elements (IREs) present in the 5' untranslated region of the mRNAs of ferritin (composed of heavy and light subunits, FTH1 and FTL) and the erythroid form of aminolevulinic acid synthase (ALAD) and in the 3' untranslated region of the mRNA of the transferrin receptor (TFRC). Binding of ACO1 or IREB2 prevents translation of FTH1:FTL and ALAD and protects the mRNA of TFRC from degradation. ACO1 and IREB2 perform an important metabolic function in response to low intracellular iron levels by interacting with iron protein mRNAs to increase net iron uptake (via TFRC) and decrease sequestration (via FT) and utilisation (via ALAD) of iron (Kaptain et al. 1991, Philpott et al. 1994, Samaniego et al. 1994).
Glutaredoxin-3 (GLRX3) is essential for both transcriptional iron regulation and intracellular iron distribution. Silencing of human Grx3 expression in HeLa cells decreases the activities of several cytosolic Fe-S proteins, for example, iron-regulatory protein 1 (ACO1), a major component of posttranscriptional iron regulation. As a consequence, Grx3-depleted cells show decreased levels of ferritin and increased levels of transferrin receptor, features characteristic of cellular iron starvation (Haunhorst et al. 2013).
Cytoplasmic aconitate hydratase (ACO1, iron regulatory protein 1, IRP1) functions either as an RNA binding protein that regulates the uptake, sequestration, and utilisation of iron or an enzyme that isomerises citrate to isocitrate, depending on changes in cellular iron levels. Under iron-replete conditions, ACO1 binds the cofactor 4Fe-4S cluster and acts as an aconitase, isomerising citrate (CIT) to isocitrate (ISCIT) (Kaptain et al. 1991, Philpott et al. 1994, Dupuy et al. 2006).
Mitochondrial ferritin (FTMT) is specifically taken up by the mitochondria and processed to a mature protein that assembles into functional ferritin shells. It is a homooligomer of 24 subunits, is roughly spherical and contains a central cavity into which the mineral iron core is deposited. FTMT possesses ferroxidase activity. Iron is taken up in the ferrous form (Fe2+) and deposited as ferric hydroxide (Fe(3+)O(OH)) after oxidation. FTMT may play an important role in the regulation of iron homeostasis in the mitochondrion (Levi et al. 2001, Langlois d'Estaintot et al. 2004).
Cellular iron homeostasis is maintained by the coordinate posttranscriptional regulation of iron metabolism genes. The E3 ubiquitin ligase complex containing the F-box/LRR-repeat protein 5 (FBXL5) protein (SKP1:FBXL5:CUL1:NEDD8) targets iron-responsive element-binding protein 2 (IREB2) for proteasomal degradation in iron-replete cells (Vashisht et al. 2009, Salahudeen et al. 2009). Cullin-1 (CUL1) is in neddylated form (NEDD8) which allows it to associate with this complex.
Cullin-associated NEDD8-dissociated protein 1 (CANDI, TIP120) is a key assembly factor of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complexes, acting as a F-box protein exchange factor. CANDI binds cullin-1 (CUL1), preventing its association with SKP1 thereby disrupting the formation of SCF complexes. Neddylated CUL1 prevents CANDI binding (Zheng et al. 2002, Goldenberg et al. 2004).
Transferrin receptor 2 (TFR2) is highly expressed in liver and erythroid precursor cells and is a close homologue of human transferrin receptor 1 (TFRC). Transferrin (TF), loaded with iron (holoTF), transports two ferric iron ions through the blood. Two holoTFs bind to a TFR2 dimer (with lower affinity than to TFRC) and mediates cellular uptake of holoTF in a non-iron dependent manner (Kawabata et al. 1999, Trinder & Baker 2003). Defects in TFR2 can cause hemochromatosis 3 (HFE3; MIM:604250), an iron metabolism disorder characterised by iron overload. Excess iron is deposited over decades in a variety of organs leading to their failure, resulting in serious illnesses including cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis and hypogonadotropic hypogonadism (Camaschella et al. 2000, Wallace & Subramaniam 2007).
Transferrin, in dimeric form (TFRC dimer), mediates cellular uptake of transferrin-bound iron in a non-iron dependent manner. Hereditary hemochromatosis protein (HFE) binds to TFRC dimer and reduces its affinity for iron-loaded transferrin (Feder et al. 1998).
Cellular iron homeostasis is maintained by the coordinate posttranscriptional regulation of iron metabolism genes. The E3 ubiquitin ligase complex comprising the F-box/LRR-repeat protein 5 (FBXL5) protein, S-phase kinase-associated protein 1 (SKP1), cullin 1 (CUL1) and NEDD8. This complex targets iron-responsive element-binding protein 2 (IREB2) for proteasomal degradation in iron-replete cells (Vashisht et al. 2009, Salahudeen et al. 2009). Here, CUL1, FBXF5 and SKP1 bind.
Cellular iron homeostasis is maintained by the coordinate posttranscriptional regulation of iron metabolism genes. The E3 ubiquitin ligase complex comprising the F-box/LRR-repeat protein 5 (FBXL5) protein, S-phase kinase-associated protein 1 (SKP1), cullin 1 (CUL1) and NEDD8. NEDD8 (Neddylin, Neural precursor cell expressed developmentally down-regulated protein 8) is a ubiquitin-like protein which plays an important role in cell cycle control and embryogenesis. NEDD8 covalently attachs to cullins (eg CUL1) and activates their associated E3-ubiquitin ligase activity thus promoting polyubiquitination and proteasomal degradation of cyclins and other regulatory proteins (Hori et al. 1999).
SLC40A1 (MTP1 aka ferroportin or IREG1) is highly expressed on macrophages where it mediates iron efflux from the breakdown of haem (Schimanski et al. 2005). SLC40A1 colocalizes with ceruloplasmin (CP) which stablizes SLC40A1 and is necessary for the efflux reaction to occur (Texel et al. 2008). Six copper ions are required as cofactor. Ceruloplasmin (CP) also catalyses the conversion of iron from ferrous (Fe2+) to ferric form (Fe3+), thereby assisting in its transport in the plasma in association with transferrin, which can only carry iron in the ferric state. As well as being expressed on macrophages, SLC40A1 is also highly expressed in the duodenum, placenta (where it may mediate the transport of iron from maternal to foetal circulation), muscle and spleen.
Cytochrome b reductase 1 not only reduces ferrous iron in the brush-border membrane but also in the airways. It is upregulated on iron starvation. However, its electron donor molecule is still unknown (Oakhill et al, 2007; Turi et al, 2006).
The iron ions that are no longer bound to transferrin are reduced by the metalloreductase STEAP3, an endosomal membrane protein. The electron donor partner of the enzyme is unknown (Ohgami et al, 2005; Ohgami et al, 2006).
Acidification of the endosome does not continue further, and the endosome fuses again with the plasma membrane (Willingham et al, 1984; Harding et al, 1983).
After about 15 minutes on the cell surface, the equilibrium favors dissociation of transferrin, and the transferrin receptor 1 dimer is available again for binding (Hemadi et al., 2006).
The function of V-type proton pumping ATPases is basically the same as that of F-type ATPases, except that V-ATPases cannot synthesize ATP from the proton motive force, the reverse reaction of pumping. When pumping, ATP hydrolysis drives a 120 degree rotation of the rotor which leads to movement of three protons into the phagosome (Adachi et al. 2007).
Uptake of iron from meat happens in the form of ferriheme, and via the same transporter that is used for folate. The process is more effective than taking up iron ions (Shayeghi M et al, 2005).
Transferrin (TF) is the main transporter of iron in the blood. The apo-form of TF can take up two ferric iron ions (Fe3+) to form holoTF (Wally et al. 2006).
In tissues other than the duodenum, ceruloplasmin (CP), in complex with SLC40A1 and 6 copper ions, oxidises ferrous iron (Fe2+) to ferric iron (Fe3+) after it is exported from the cell (Sato et al. 1990).
Heme is utilised as a prosthetic group in the production of hemoproteins inside cells. However, when intracellular heme accumulation occurs, heme is able to exert its pro-oxidant and cytotoxic action. The amount of free heme must be tightly controlled to maintain cellular homeostasis and avoid pathological conditions (Chiabrando et al. 2014). The heme transporter FLVCR is expressed in intestine and liver tissue, but also in developing erythroid cells where it is required to protect them from heme toxicity (Quigley et al, 2004; Rey et al, 2008). Two different isoforms have been described. FLVCR1-1 (FLVCR1a) resides in the plasma membrane and is responsible for heme detoxification in several cell types, such as erythroid progenitors, endothelial cells, hepatocytes, lymphocytes and intestinal cells.
Hephaestin oxidizes ferrous iron (Fe2+) to ferric iron (Fe3+) after export from duodenal cells to enable its transport via transferrin (Griffiths et al, 2005).
Mucolipin-1 is an iron ion channel specifically expressed in endosome and lysosome membranes. It catalyzes the diffusion of Fe2+ ions into the cytosol (Dong et al, 2008).
Heme is utilised as a prosthetic group in the production of hemoproteins inside cells. However, when intracellular heme accumulation occurs, heme is able to exert its pro-oxidant and cytotoxic action. The amount of free heme must be tightly controlled to maintain cellular homeostasis and avoid pathological conditions (Chiabrando et al. 2014). The tetrameric efflux pump ATP-binding cassette sub-family G member 2 (ABCG2) (Xu et al. 2004) can relieve cells from toxic heme concentrations even against a concentration gradient. It is expressed in placenta, liver, and small intestine (Krishnamurthy et al. 2004, Doyle & Ross 2003, Zhang et al. 2003).
Transferrin receptor 1 (TFRC) molecules can be found on the outside of any cell. Transferrin (TF), loaded with iron (holoTF), transports two ferric iron ions through the blood and two holoTFs bind to a TFRC dimer, which mediates cellular uptake of holoTF in a non-iron dependent manner (West et al. 2001).
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ALAD, FTL, FTH1
mRNAsThe functional molecule forms a roughly spherical shell with a diameter of 12 nm and contains a central cavity into which the insoluble mineral iron core is deposited. Iron metabolism provides a useful example of gene expression translational control. Increased iron levels stimulate the synthesis of the iron-binding protein, ferritin, without any corresponding increase in the amount of ferritin mRNA. The 5'-UTR of both ferritin heavy chain mRNA and light chain mRNA contain a single iron-response element (IRE), a specific cis-acting regulatory sequence which forms a hairpin structure.
Annotated Interactions
ALAD, FTL, FTH1
mRNAsThe human gene SLC40A1 encodes the metal transporter protein MTP1 (aka ferroportin or IREG1). This protein resides on the basolateral membrane of enterocytes and mediates ferrous iron efflux into the portal vein (Schimanski et al. 2005). MTP1 colocalizes with hephaestin (HEPH) which stablizes MTP1 and is necessary for the efflux reaction to occur (Han & Kim 2007, Chen et al. 2009). As well as the dudenum, MTP1 is also highly expressed on macrophages (where it mediates iron efflux from the breakdown of haem) and the placenta (where it may mediate the transport of iron from maternal to foetal circulation). It is also expressed in muscle and spleen.
Under iron-replete conditions, ACO1 binds the cofactor 4Fe-4S cluster and acts as an aconitase, isomerising citrate (CIT) to isocitrate (ISCIT) (Kaptain et al. 1991, Philpott et al. 1994, Dupuy et al. 2006).
During iron scarcity, ACO1 and iron-responsive element-binding protein 2 (IREB2) bind with high affinity to RNA stem-loops known as iron-responsive elements (IREs) present in the 5' untranslated region of the mRNAs of ferritin (composed of heavy and light subunits, FTH1 and FTL) and the erythroid form of aminolevulinic acid synthase (ALAD) and in the 3' untranslated region of the mRNA of the transferrin receptor (TFRC). Binding of ACO1 or IREB2 prevents translation of FTH1:FTL and ALAD and protects the mRNA of TFRC from degradation. ACO1 and IREB2 perform an important metabolic function in response to low intracellular iron levels by interacting with iron protein mRNAs to increase net iron uptake (via TFRC) and decrease sequestration (via FT) and utilisation (via ALAD) of iron (Kaptain et al. 1991, Philpott et al. 1994, Samaniego et al. 1994).
Glutaredoxin-3 (GLRX3) is essential for both transcriptional iron regulation and intracellular iron distribution. Silencing of human Grx3 expression in HeLa cells decreases the activities of several cytosolic Fe-S proteins, for example, iron-regulatory protein 1 (ACO1), a major component of posttranscriptional iron regulation. As a consequence, Grx3-depleted cells show decreased levels of ferritin and increased levels of transferrin receptor, features characteristic of cellular iron starvation (Haunhorst et al. 2013).