Iron uptake and transport (Homo sapiens)
From WikiPathways
Description
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).
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=917937
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Ontology Terms
Saving...Bibliography
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- Sato M, Schilsky ML, Stockert RJ, Morell AG, Sternlieb I.; ''Detection of multiple forms of human ceruloplasmin. A novel Mr 200,000 form.''; PubMed Europe PMC Scholia
- Harding C, Heuser J, Stahl P.; ''Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes.''; PubMed Europe PMC Scholia
- Willingham MC, Hanover JA, Dickson RB, Pastan I.; ''Morphologic characterization of the pathway of transferrin endocytosis and recycling in human KB cells.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
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- Han O, Kim EY.; ''Colocalization of ferroportin-1 with hephaestin on the basolateral membrane of human intestinal absorptive cells.''; PubMed Europe PMC Scholia
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- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Kurz T, Terman A, Gustafsson B, Brunk UT.; ''Lysosomes in iron metabolism, ageing and apoptosis.''; PubMed Europe PMC Scholia
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- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Devireddy LR, Gazin C, Zhu X, Green MR.; ''A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake.''; PubMed Europe PMC Scholia
- Xu J, Liu Y, Yang Y, Bates S, Zhang JT.; ''Characterization of oligomeric human half-ABC transporter ATP-binding cassette G2.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Hower V, Mendes P, Torti FM, Laubenbacher R, Akman S, Shulaev V, Torti SV.; ''A general map of iron metabolism and tissue-specific subnetworks.''; PubMed Europe PMC Scholia
- Hémadi M, Ha-Duong NT, El Hage Chahine JM.; ''The mechanism of iron release from the transferrin-receptor 1 adduct.''; PubMed Europe PMC Scholia
- Doyle L, Ross DD.; ''Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2).''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
History
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External references
DataNodes
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| 2GABRA
2GABRB GABRG GABA | REACT_25130 (Reactome)  | |||
| ABCG2 dimer | REACT_25155 (Reactome) | |||
| ADP | Arrow | REACT_115892 (Reactome) | ||
| ADP | Arrow | REACT_24963 (Reactome) | ||
| ADP | Arrow | REACT_24989 (Reactome) | ||
| ADP | Arrow | REACT_25071 (Reactome) | ||
| ADP | Arrow | REACT_25155 (Reactome) | ||
| ADP | Arrow | REACT_25173 (Reactome) | ||
| ADP | Arrow | REACT_25268 (Reactome) | ||
| ADP | Arrow | REACT_25287 (Reactome) | ||
| ADP | Arrow | REACT_25301 (Reactome) | ||
| AMP | Arrow | REACT_160256 (Reactome) | ||
| ANOs | REACT_160277 (Reactome) | |||
| APLs | Arrow | REACT_115892 (Reactome) | ||
| APLs | Arrow | REACT_24989 (Reactome) | ||
| APLs | REACT_115892 (Reactome) | |||
| APLs | REACT_24989 (Reactome) | |||
| ASIC trimer H+ | REACT_160227 (Reactome) | |||
| ASIC4 | TBar | REACT_160227 (Reactome) | ||
| ATP1A
ATP1B FXYD | REACT_25287 (Reactome) | |||
| ATP2A1-3 | REACT_23784 (Reactome) | |||
| ATP2A1-3 | REACT_25316 (Reactome) | |||
| ATP2B1-4 | REACT_23956 (Reactome) | |||
| ATP2C1/2 Mg2+ | REACT_25301 (Reactome) | |||
| ATP4A/12A ATP4B | REACT_25173 (Reactome) | |||
| ATP7A | REACT_25071 (Reactome) | |||
| ATP7B | REACT_24963 (Reactome) | |||
| ATP | Arrow | REACT_160216 (Reactome) | ||
| ATP | REACT_115892 (Reactome) | |||
| ATP | REACT_160256 (Reactome) | |||
| ATP | REACT_24963 (Reactome) | |||
| ATP | REACT_24989 (Reactome) | |||
| ATP | REACT_25071 (Reactome) | |||
| ATP | REACT_25155 (Reactome) | |||
| ATP | REACT_25173 (Reactome) | |||
| ATP | REACT_25268 (Reactome) | |||
| ATP | REACT_25287 (Reactome) | |||
| ATP | REACT_25301 (Reactome) | |||
| BESTs | REACT_160081 (Reactome) | |||
| BESTs | REACT_160220 (Reactome) | |||
| BV | Arrow | REACT_22100 (Reactome) | ||
| CLCN1/2/KA/KB | REACT_160109 (Reactome) | |||
| CLCN3 | REACT_160116 (Reactome) | |||
| CLCN4/5/6 | REACT_160268 (Reactome) | |||
| CLCN7 OSTM1 | REACT_160230 (Reactome) | |||
| CLIC2 | TBar | REACT_160216 (Reactome) | ||
| CO | Arrow | REACT_22100 (Reactome) | ||
| CYBRD1 Heme | REACT_25114 (Reactome) | |||
| Ca2+ | Arrow | REACT_160216 (Reactome) | ||
| Ca2+ | Arrow | REACT_160220 (Reactome) | ||
| Ca2+ | Arrow | REACT_160263 (Reactome) | ||
| Ca2+ | Arrow | REACT_160277 (Reactome) | ||
| Ca2+ | Arrow | REACT_23784 (Reactome) | ||
| Ca2+ | Arrow | REACT_25246 (Reactome) | ||
| Ca2+ | Arrow | REACT_25301 (Reactome) | ||
| Ca2+ | Arrow | REACT_25316 (Reactome) | ||
| Ca2+ | REACT_23784 (Reactome) | |||
| Ca2+ | REACT_25246 (Reactome) | |||
| Ca2+ | REACT_25301 (Reactome) | |||
| Ca2+ | REACT_25316 (Reactome) | |||
| Ca2+ | TBar | REACT_160155 (Reactome) | ||
| Cl- | Arrow | REACT_160116 (Reactome) | ||
| Cl- | Arrow | REACT_160230 (Reactome) | ||
| Cl- | Arrow | REACT_160268 (Reactome) | ||
| Cl- | REACT_160116 (Reactome) | |||
| Cl- | REACT_160230 (Reactome) | |||
| Cl- | REACT_160268 (Reactome) | |||
| Cu2+ | Arrow | REACT_24963 (Reactome) | ||
| Cu2+ | Arrow | REACT_25071 (Reactome) | ||
| Cu2+ | REACT_24963 (Reactome) | |||
| Cu2+ | REACT_25071 (Reactome) | |||
| Fe2+ | Arrow | REACT_20526 (Reactome) | ||
| Fe2+ | Arrow | REACT_22100 (Reactome) | ||
| Fe2+ | REACT_115629 (Reactome) | |||
| Fe2+ | REACT_20526 (Reactome) | |||
| Fe2+ | REACT_25098 (Reactome) | |||
| Fe2+ | REACT_25198 (Reactome) | |||
| Fe3+ | Arrow | REACT_115629 (Reactome) | ||
| Fe3+ | Arrow | REACT_25098 (Reactome) | ||
| Fe3+ | Arrow | REACT_25198 (Reactome) | ||
| Fe3+ | Arrow | REACT_25277 (Reactome) | ||
| Fe3+ | REACT_24919 (Reactome) | |||
| Fe3+ | REACT_25114 (Reactome) | |||
| Fe3+ | REACT_25385 (Reactome) | |||
| Ferritin Complex | REACT_115629 (Reactome) | |||
| GABRR pentamer GABA | REACT_25391 (Reactome) | |||
| GLRA
GLRB Gly | REACT_25304 (Reactome) | |||
| H+ | Arrow | REACT_160116 (Reactome) | ||
| H+ | Arrow | REACT_160226 (Reactome) | ||
| H+ | Arrow | REACT_160230 (Reactome) | ||
| H+ | Arrow | REACT_160252 (Reactome) | ||
| H+ | Arrow | REACT_160268 (Reactome) | ||
| H+ | Arrow | REACT_160312 (Reactome) | ||
| H+ | Arrow | REACT_20526 (Reactome) | ||
| H+ | Arrow | REACT_23784 (Reactome) | ||
| H+ | Arrow | REACT_25173 (Reactome) | ||
| H+ | Arrow | REACT_25268 (Reactome) | ||
| H+ | Arrow | REACT_25316 (Reactome) | ||
| H+ | REACT_115629 (Reactome) | |||
| H+ | REACT_160116 (Reactome) | |||
| H+ | REACT_160226 (Reactome) | |||
| H+ | REACT_160230 (Reactome) | |||
| H+ | REACT_160252 (Reactome) | |||
| H+ | REACT_160268 (Reactome) | |||
| H+ | REACT_160312 (Reactome) | |||
| H+ | REACT_20526 (Reactome) | |||
| H+ | REACT_23784 (Reactome) | |||
| H+ | REACT_25098 (Reactome) | |||
| H+ | REACT_25173 (Reactome) | |||
| H+ | REACT_25198 (Reactome) | |||
| H+ | REACT_25268 (Reactome) | |||
| H+ | REACT_25316 (Reactome) | |||
| H2O | Arrow | REACT_115629 (Reactome) | ||
| H2O | Arrow | REACT_22100 (Reactome) | ||
| H2O | Arrow | REACT_25098 (Reactome) | ||
| H2O | Arrow | REACT_25198 (Reactome) | ||
| H2O | REACT_115892 (Reactome) | |||
| H2O | REACT_24963 (Reactome) | |||
| H2O | REACT_24989 (Reactome) | |||
| H2O | REACT_25071 (Reactome) | |||
| H2O | REACT_25155 (Reactome) | |||
| H2O | REACT_25173 (Reactome) | |||
| H2O | REACT_25268 (Reactome) | |||
| H2O | REACT_25287 (Reactome) | |||
| H2O | REACT_25301 (Reactome) | |||
| HMOX1/2 | REACT_22100 (Reactome) | |||
| HTR3 5HT | REACT_25246 (Reactome) | |||
| K+ | Arrow | REACT_25173 (Reactome) | ||
| K+ | Arrow | REACT_25246 (Reactome) | ||
| K+ | Arrow | REACT_25287 (Reactome) | ||
| K+ | REACT_25173 (Reactome) | |||
| K+ | REACT_25246 (Reactome) | |||
| K+ | REACT_25287 (Reactome) | |||
| MCOLN1 | REACT_25069 (Reactome) | |||
| MTP1
CP 6Cu2+ | REACT_23996 (Reactome) | |||
| MTP1
CP 6Cu2+ | REACT_25098 (Reactome) | |||
| MTP1
HEPH 6Cu2+ | REACT_20531 (Reactome) | |||
| MTP1
HEPH 6Cu2+ | REACT_25198 (Reactome) | |||
| NAADP | Arrow | REACT_160271 (Reactome) | ||
| NADP+ | Arrow | REACT_22100 (Reactome) | ||
| NADPH | REACT_22100 (Reactome) | |||
| NALCN
UNC79 UNC80 | REACT_160155 (Reactome) | |||
| NSAID | TBar | REACT_160227 (Reactome) | ||
| Na+/Li+ | Arrow | REACT_160252 (Reactome) | ||
| Na+/Li+ | REACT_160252 (Reactome) | |||
| Na+ | Arrow | REACT_160084 (Reactome) | ||
| Na+ | Arrow | REACT_160226 (Reactome) | ||
| Na+ | Arrow | REACT_160312 (Reactome) | ||
| Na+ | Arrow | REACT_25246 (Reactome) | ||
| Na+ | Arrow | REACT_25287 (Reactome) | ||
| Na+ | REACT_160084 (Reactome) | |||
| Na+ | REACT_160226 (Reactome) | |||
| Na+ | REACT_160312 (Reactome) | |||
| Na+ | REACT_25246 (Reactome) | |||
| Na+ | REACT_25287 (Reactome) | |||
| O2 | REACT_115629 (Reactome) | |||
| O2 | REACT_22100 (Reactome) | |||
| O2 | REACT_25098 (Reactome) | |||
| O2 | REACT_25198 (Reactome) | |||
| P-type ATPases type IV | REACT_115892 (Reactome) | |||
| P-type ATPases type IV | REACT_24989 (Reactome) | |||
| PPi | Arrow | REACT_160256 (Reactome) | ||
| Pi | Arrow | REACT_115892 (Reactome) | ||
| Pi | Arrow | REACT_160084 (Reactome) | ||
| Pi | Arrow | REACT_24963 (Reactome) | ||
| Pi | Arrow | REACT_24989 (Reactome) | ||
| Pi | Arrow | REACT_25071 (Reactome) | ||
| Pi | Arrow | REACT_25155 (Reactome) | ||
| Pi | Arrow | REACT_25173 (Reactome) | ||
| Pi | Arrow | REACT_25268 (Reactome) | ||
| Pi | Arrow | REACT_25287 (Reactome) | ||
| Pi | Arrow | REACT_25301 (Reactome) | ||
| Pi | REACT_160084 (Reactome) | |||
| RAF1
SGK TSC22D3 WPP | REACT_160256 (Reactome) | |||
| REACT_115629 (Reactome) | Ferritin oxidises Fe(II) ions to Fe(III), migrates them to its centre, and collects thousands of them as FeO(OH) in the central mineral core from which they can be later remobilised (Harrison & Arrosio 1996). | |||
| REACT_115892 (Reactome) | The plasma membrane contains a broad range of lipids making up the bilayer. Aminophospholipids (APLs) such as phosphatidylserine (PS) and phosphatidylethanolamine (PE) are distributed in this bilayer and their arrangement is mediated by the P-type ATPases type IV family (Paulusma and Oude Elferink, 2005). | |||
| REACT_160081 (Reactome) | Many Cl- channels such as CFTR, ClC, CaCC, and ligand-gated anion channels are permeable to bicarbonate (HCO3-) which is an important anion in the regulation of pH. Many tissues, including retinal pigment epithelium (RPE), utilize HCO3- transporters to mediate transport of HCO3-. Bestrophns 1-4 (BEST1-4, aka vitelliform macular dystrophy proteins) have high permeability to HCO3- (Hu & Hartzell 2008). Defective BEST1 may play a role in macular degeneration in the eye due to impaired HCO3- and Cl- conductance (Hu & Hartzell 2008). | |||
| REACT_160084 (Reactome) | The microsomal Na+/(PO4)3- transporter isoform 1 (SLC17A3, NPT4 isoform 1) is a member of the anion-cation symporter family. It is expressed in liver, kidney and intestine and may function as a cotransporter of sodium (Na+) and phosphate ((PO4)3- or Pi) across the ER membrane (Melis et al. 2004). | |||
| REACT_160095 (Reactome) | Amiloride-sensitive sodium channels (SCNNs, aka ENaCs, epithelial Na+ channels, non voltage-gated sodium channels) belong to the epithelial Na+ channel/degenerin (ENaC/DEG) protein family and mediate the transport of Na+ (and associated water) through the apical membrane of epithelial cells in kidney, colon and lungs. This makes SCNNs important determinants of systemic blood pressure. The physiological activator for SCNNs is unknown but as they belong in the same family as acid-sensitive ion channels (ASICs, which are mediated by protons), these may also be the activating ligands for SCNNs. SCNNs are probable heterotrimers comprising an alpha (or interchangeable delta subunit), beta and gamma subunit (Horisberger 1998). | |||
| REACT_160104 (Reactome) | Human serum urate levels are largely maintained by its reabsorption and secretion in the kidney. Loss of this maintenance can elevate urate levels leading to gout, hypertension, and various cardiovascular diseases. Renal urate reabsorption is controlled via two proximal tubular urate transporters; apical SLC22A12 (URAT1) and basolateral SLC2A9 (URATv1, GLUT9). On the other hand, urate secretion is mediated by the orphan sodium phosphate transporter 4 isoform 2 (SLC17A3, NPT4 isoform 2). It is mainly expressed at the apical side of renal tubules and functions as a voltage-driven urate transporter (Jutabha et al. 2010). Genetic variations in SLC17A3 influence the variance in serum uric acid concentrations and define the serum uric acid concentration quantitative trait locus 4 (UAQTL4; MIM:612671). Excess serum urate (hyperuricemia) can lead to the development of gout, characterized by tissue deposition of monosodium urate crystals. | |||
| REACT_160109 (Reactome) | Chloride channel proteins 1, 2, Ka and Kb (CLCN1, 2, KA, KB) can mediate Cl- influx across the plasma membrane of almost all cells. CLCN1 is expressed mainly on skeletal muscle where it is involved in the electrical stability of the muscle. CLCN1 is thought to function in a homotetrameric form (Steimeyer et al. 1994). CLCN2 is ubiquitously expressed, playing a role in the regulation of cell volume (Cid et al. 1995, Niemeyer et al. 2009). Defects in CLCN1 cause myotonia congenita, an autosomal dominant disease (MCD aka Thomsen disease, MIM:160800). It is characterized by muscle stiffness due to delayed relaxation, resulting from membrane hyperexcitability (Meyer-Kleine et al. 1995, Steimeyer et al. 1994). Defects in CLCN1 also cause autosomal recessive myotonia congenita (MCR aka Becker disease, MIM:255700) (Koch et al. 1992, Meyer-Kleine et al. 1995), a nondystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction. Becker disease is more common and more severe than Thomsen disease. CLCNKA and B (Kieferle et al. 1994) are predominantly expressed in distal nephron segments of the kidney (Takeuchi et al. 1995) and the inner ear (Estevez et al. 2001, Schlingmann et al. 2004). They are tightly associated with their essential beta subunit barttin (BSND), requiring it to be fully functional channels (Fischer et al. 2010, Scholl et al. 2006). These channels bound to BSND are essential for renal Cl- reabsorption (Waldegger & Jentsch 2000) and K+ recycling in the inner ear (Estevez et al. 2001). Defects in CLCNKA and B cause Bartter syndrome type 4B (BS4B; MIM:613090) characterized by impaired salt reabsorption and sensorineural deafness (Schlingmann et al. 2004, Nozu et al. 2008). Defects in BSND cause Bartter syndrome type 4A (BS4A aka infantile Bartter syndrome with sensorineural deafness; MIM:602522) characterized by impaired salt reabsorption in the thick ascending loop of Henle and sensorineural deafness (Birkenhager et al. 2001, Nozu et al. 2008). | |||
| REACT_160116 (Reactome) | The H+/Cl- exchange transporter CLCN3 (Borsani et al. 1995) mediates the exchange of endosomal Cl- for cytosolic H+ across late endosomal membranes, contributing to the acidification of endosomes. The activity of CLCN3 is inferred from experiments in mice (Stobrawa et al. 2001, Hara-Chikuma et al. 2005). | |||
| REACT_160155 (Reactome) | The sodium leak channel non-selective protein NALCN, a nonselective cation channel, forms the background Na+ leak conductance and controls neuronal excitability (Lu et al. 2007). Mice with mutant NALCN have a severely disrupted respiratory rhythm and die within 24 hours of birth. Calcium (Ca2+) influences neuronal excitability via the NALCN:UNC79:UNC80 complex, with high Ca2+ concentrations inhibiting transport of Na+ (Lu et al. 2010). | |||
| REACT_160181 (Reactome) | Protein tweety homolog 1 (TTYH1) has 5 isoforms. Isoform 3 (Campbell et al. 2000) mediates the Ca+-independent efflux of Cl- across plasma membranes (Suzuki & Mizuno 2004, Suzuki 2006). | |||
| REACT_160216 (Reactome) | Ryanodine receptors (RYRs) are located in the sarcoplasmic reticulum (SR) membrane and mediate the release of Ca2+ from intracellular stores during excitation-contraction (EC) coupling in both cardiac and skeletal muscle. RYRs are the largest known ion channels (>2MDa) and are functional in their homotetrameric forms. There are three mammalian isoforms (RYR1-3); RYR1 is prominent in skeletal muscle (Zorzato et al. 1990), RYR2 in cardiac muscle (Tunwell et al. 1996) and RYR3 is found in the brain (Nakashima et al. 1997). For review see Lanner et al. 2010. The function of RYRs are controlled by intracellular Ca2+-binding proteins calsequestrin 1 and 2 (CASQ1 and 2) and the anchoring proteins triadin (TRDN) and junctin. Together, they make up the Ca2+-release complex. CASQ1 and 2 buffer intra-SR Ca2+ stores in skeletal muscle and cardiac muscle respectively (Fujii et al. 1990, Kim et al. 2007). When Ca2+ concentrations reach 1mM, CASQs polymerize (Kim et al. 2007) and can attach to one end of RYRs, mediated by anchoring proteins TRDN and junctin (Taske et al. 1995). By sequestering Ca2+ ions, CASQs can inhibit RYRs function. For reviews see Beard et al. 2004, Beard et al. 2009a, Beard et al. 2009b. A member of the intracellular Cl- channel protein family, CLIC2, has also been determined to inhibit RYR-mediated Ca2+ transport (Board et al. 2004), potentially playing a role in the homeostasis of Ca2+ release from intracellular stores. Inhibition is thought to be via reducing activation of the channels by their primary endogenous cytoplasmic ligands, ATP and Ca2+ (Dulhunty et al. 2005). | |||
| REACT_160220 (Reactome) | Bestrophins 1-4 (BEST1-4, aka vitelliform macular dystrophy proteins) mediate cytosolic Cl- efflux across plasma membranes. This transport is sensitive to intracellular Ca2+ concentrations (Sun et al. 2002, Tsunenari et al. 2003). Mutations in bestrophins that impair their function are implicated in macular degeneration in the eye. Defects in BEST1 cause vitelliform macular dystrophy (BVMD, Best's disease, MIM:153700), an autosomal dominant form of macular degeneration that usually begins in childhood and is characterized lesions due to abnormal accumulation of lipofuscin within and beneath retinal pigment epithelium (RPE) cells (Marquardt et al. 1998, Petrukhin et al. 1998). | |||
| REACT_160226 (Reactome) | The sperm-specific Na+/H+ exchanger SLC9C1 (aka sodium/hydrogen exchanger 10, NHE10) is localized to the flagellar membrane and is involved in pH regulation of spermatozoa required for sperm motility and fertility. The activity of human SLC9C1 is inferred from experiments using mouse Slc9c1 (Wang et al. 2003). | |||
| REACT_160227 (Reactome) | Acid-sensing ion channels 1, 2, 3 and 5 (ASIC1, 2, 3 and 5, aka amiloride-sensitive cation channels) are homotrimeric, multi-pass membrane proteins which can transport sodium (Na+) when activated by extracellular protons. Members of the ASIC family are sensitive to amiloride and function in neurotransmission. The encoded proteins function in learning, pain transduction, touch sensation, and development of memory and fear. Many neuronal diseases cause acidosis, accompanied by pain and neuronal damage; ASICs can mediate the pathophysiological effects seen in acidiosis (Wang & Xu 2011, Qadri et al. 2012). The diuretic drug amiloride inhibits these channels, resulting in analgesic effects. NSAIDs (Nonsteroidal anti-inflammatory drugs) can also inhibit ASICs to produce analgesia (Voilley et al. 2001). ASICs are also partially permeable to Ca2+, Li+ and K+ (not shown here). ASIC1 and 2 are expressed mostly in brain (Garcia-Anoveros et al. 1997, Price et al. 1996), ASIC3 is strongly expressed in testis (de Weille et al. 1998, Ishibashi & Marumo 1998) and ASIC5 is found mainly in intestine (Schaefer et al. 2000). ASIC4 subunits do not form functional channels and it's activity is unknown. It could play a part in regulating other ASIC activity (Donier et al. 2008). | |||
| REACT_160230 (Reactome) | Chloride channel 7 comprises H+/Cl- exchange transporter 7 (CLCN7) and osteopetrosis-associated transmembrane protein 1 (OSTM1) (Leisle et al. 2011). This complex localises to the lysosomal membrane where it mediates the exchange of Cl- and H+ ions, perhaps playing a role in the acidification of the lysosome (Graves et al. 2008). Defects in CLCN7 cause osteopetrosis autosomal recessive types 2 and 4 (OPTB2, MIM:166600 and OPTB4, MIM:611490) (Frattini et al. 2003, Pangrazio et al. 2010). Defects in OSTM1 cause osteopetrosis autosomal recessive type 5 (OPTB5, MIM:259720) (Pangrazio et al. 2006). | |||
| REACT_160252 (Reactome) | Mitochondrial sodium/hydrogen exchanger 9B2 (SLC9B2, aka NHA2) is ubiquitously expressed and mediates the electrogenic exchange of 1 Na+ (or 1 Li+) for 2 H+ across the inner mitochondrial membrane (Xiang et al. 2007, Taglicht et al. 1993). This transport is thought to play a role in salt homeostasis and pH regulation in humans. | |||
| REACT_160256 (Reactome) | Amiloride-sensitive sodium channels (SCNNs, aka ENaCs, epithelial Na+ channels, non voltage-gated sodium channels) comprises three subunits (alpha, beta and gamma) and plays an essential role in Na+ and fluid absorption in the kidney, colon and lung. The number of channels at the cell's surface (consequently its function) can be regulated. This is achieved by ubiquitination of SCNN via E3 ubiquitin-protein ligases (NED4L and WPP1) (Staub et al. 2000, Farr et al. 2000). NED4L/WPP1 is found in a signaling complex including Raf1 (RAF proto-oncogene serine/threonine-protein kinase), SGK (serum/glucocorticoid-regulated kinase) and GILZ (glucocorticoid-induced leucine zipper protein, TSC22D3) (Soundararajan et al. 2009). Ubiquitinated SCNN (Ub-SCNN) is targeted for degradation so a lesser number of channels are present at the cell surface, reducing the amount of Na+ absorption. Proline-rich sequences at the C-terminus of SCNNs include the PY motif containing a PPxY sequence. PY motifs bind WW domains of NED4L/WPP1. Protein kinases with no lysine K (WNKs) can activate SCNN activity by interacting non-enzymatically with the signaling complex, specifically SGK although the mechanism is unknown (Heise et al. 2010). | |||
| REACT_160263 (Reactome) | Human homologues 2 and 3 (TTYH2 and 3) mediate the efflux of Cl- from cells in response to the increase in intracellular Ca2+ levels (Suzuki & Mizuno 2004, Suzuki 2006). | |||
| REACT_160268 (Reactome) | The H+/Cl- exchange transporters CLCN4 (Kawasaki et al. 1999, Zdebik et al. 2008), CLCN5 (Zdebik et al. 2008) and CLCN6 (Neagoe et al. 2010) mediate the exchange of endosomal Cl- for cytosolic H+ across endosomal membranes, contributing to the acidification of endosomes. | |||
| REACT_160271 (Reactome) | Calcium (Ca2+) can be mobilised from intracellular stores by the presence of nicotinic acid adenine dinucleotide phosphate (NAADP). Two pore calcium channel proteins 1 and 2 (TPCN1 and 2) are expressed on endosomal (not shown here) and lysosomal membranes and mediate the mobilization of Ca2+ from these organelles when activated by NAADP (Brailoiu et al. 2009, Calcraft et al. 2009). | |||
| REACT_160277 (Reactome) | Calcium-activated chloride channels (CaCCs) are ubiquitously expressed and implicated in physiological processes such as sensory transduction, fertilization, epithelial secretion, and smooth muscle contraction. The anoctamin family of transmembrane proteins (ANO, TMEM16) belong to CaCCs and have been shown to transport Cl- ions when activated by intracellular Ca2+ (Galietta 2009, Huang et al. 2012). There are currently 10 members, ANO1-10, all having a similar structure, with eight putative transmembrane domains and cytosolic amino- and carboxy-termini. ANO1 and 2 possess Ca2+ activated Cl- transport activity (Yang et al. 2008, Scudieri et al. 2012) while the remaining members also show some demonstrable activity (Tian et al. 2012). | |||
| REACT_160312 (Reactome) | The sodium/hydrogen exchanger 9B1 (SLC9B1 aka Na+/H+ exchanger like domain containing 1, NHEDC1) is specifically expressed on the plasma membrane of the testis and may be implicated in infertility (Ye et al. 2006). Sodium/hydrogen exchanger 9C2 (SLC9C2), also localized to the plasma membrane, may be involved in pH regulation although this protein has not been fully characterized. | |||
| REACT_20526 (Reactome) | 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). NRAMP2 resides on the apical membrane of enterocytes and mediates the uptake of ferrous iron into these cells (Tandy S et al, 2000). DCT1 can also accept a broad range of transition metal ions. | |||
| REACT_20531 (Reactome) | 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 a metal transporter protein MTP1 (also called ferroportin or IREG1). This protein resides on the basolateral membrane of enterocytes and mediates ferrous iron efflux into the portal vein (Schimanski LM et al, 2005). MTP1 colocalizes with hephaestin (HEPH) which stablizes MTP1 and is necessary for the efflux reaction to occur (Han O and Kim EY, 2007; Chen H 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. | |||
| REACT_22100 (Reactome) | 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. | |||
| REACT_23784 (Reactome) | Intracellular pools of Ca2+ serve as the source for inositol 1,4,5-trisphosphate (IP3) -induced alterations in cytoplasmic free Ca2+. In most human cells Ca2+ is stored in the lumen of the sarco/endoplastic reticulum by ATPases known as SERCAs (ATP2As). In platelets, ATP2As transport Ca2+ into the platelet dense tubular network. ATP2As are P-type ATPases, similar to the plasma membrane Na+ and Ca+-ATPases. Humans have three genes for SERCA pumps; ATP2A1-3. Studies on ATP2A1 suggest that it binds two Ca2+ ions from the cytoplasm and is subsequently phosphorylated at Asp351 before translocating Ca2+ into the SR lumen. There is a counter transport of two or possibly three protons ensuring partial charge balancing. | |||
| REACT_23956 (Reactome) | The plasma membrane Ca-ATPases 1-4 (ATP2B1-4, PMCAs) are P-type Ca2+-ATPases regulated by calmodulin. The PMCA also counter-transports a proton. PMCA is important for Ca2+ homeostasis and function. | |||
| REACT_23996 (Reactome) | MTP1 is also highly expressed on macrophages where it mediates iron efflux from the breakdown of haem. The human gene SLC40A1 encodes a metal transporter protein MTP1 (also called ferroportin or IREG1) (Schimanski LM et al, 2005). MTP1 colocalizes with ceruloplasmin (CP) which stablizes MTP1 and is necessary for the efflux reaction to occur (Texel SJ et al, 2008). Ceruloplasmin also catalyzes the conversion of iron from ferrous (Fe2+) to ferric form (Fe3+), therefore assisting in its transport in the plasma in association with transferrin, which can only carry iron in the ferric state. As well as on macrophages, MTP1 is also highly expressed in the duodenum, placenta (where it may mediate the transport of iron from maternal to foetal circulation), in muscle and the spleen. | |||
| REACT_24919 (Reactome) | 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). | |||
| REACT_24927 (Reactome) | 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). | |||
| REACT_24945 (Reactome) | Transferrin receptor 1 molecules can be found on the outside of any cell. Transferrin transports two iron ions through the blood and two transferrins bind to a TfR1 dimer (West et al, 2001). | |||
| REACT_24963 (Reactome) | The human gene ATP7B encodes the copper-transporting ATPase 2 (ATP7B, ATPase2, Wilson's protein) which is expressed mainly in the liver, brain and kidneys (Bull et al, 1993). ATP7B resides on the trans-Golgi membrane where it it thought to sequester copper from the cytosol into the golgi (Yang et al, 1997). Defects in ATP7B are the cause of Wilson disease (WD), an autosomal recessive disorder of copper metabolism characterized by the toxic accumulation of copper in a number of organs, particularly the liver and brain (Thomas et al, 1995). | |||
| REACT_24977 (Reactome) | The transferrin/receptor complex is internalized as a clathrin-coated vesicle (Willingham et al, 1984; Harding et al, 1983). | |||
| REACT_24989 (Reactome) | The plasma membrane contains a broad range of lipids making up the bilayer. Aminophospholipids such as phosphatidylserine (PS) and phosphatidylethanolamine (PE) are distributed in this bilayer and their arrangement is mediated by the P-type ATPases type IV family (Paulusma and Oude Elferink, 2005). | |||
| REACT_25025 (Reactome) | 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). | |||
| REACT_25069 (Reactome) | 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). | |||
| REACT_25071 (Reactome) | The human gene ATP7A (MNK) encodes the copper-transporting ATPase 1 (ATP7A, ATPase1, Menkes protein) which is expressed in most tissues except the liver (Vulpe et al, 1993; Chelly et al, 1993). Normally, ATP7A resides on the trans-Golgi membrane (Dierick et al, 1997). When cells are exposed to excessive copper levels, it is rapidly relocalized to the plasma membrane where it functions in copper efflux (Petris and Mercer, 1999). Defects in ATP7A are the cause of Menkes disease (MNKD), an X-linked recessive disorder of copper metabolism characterized by generalized copper deficiency (Ambrosini and Mercer, 1999). | |||
| REACT_25098 (Reactome) | In tissues other than the duodenum, ceruloplasmin oxidizes ferrous iron after it is exported from the cell (Sato et al, 1990). | |||
| REACT_25114 (Reactome) | 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). | |||
| REACT_25130 (Reactome) | The GABA(A) receptor (GABR) family belongs to the ligand-gated ion channel superfamily (LGIC). Its endogenous ligand is gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. There are six alpha subunits (GABRA) (Garrett et al. 1988, Schofield et al. 1989, Hadingham et al. 1993, Edenberg et al. 2004, Hadingham et al. 1993, Yang et al. 1995, Wingrove et al. 1992, Hadingham et al. 1996), three beta subunits (GABRB) (Schofield et al. 1989, Hadingham et al. 1993, Wagstaff et al. 1991) and 2 gamma subunits (GABRG) (Khan et al. 1993, Hadingham et al. 1995) characterized. GABA(A) functions as a heteropentamer, the most common structure being 2 alpha subunits, 2 beta subunits and a gamma subunit (2GABRA:2GABRB:GABRG). Upon binding of GABA, this complex conducts chloride ions through its pore, resulting in hyperpolarization of the neuron. This causes an inhibitory effect on neurotransmission by reducing the chances of a successful action potential occurring. | |||
| REACT_25155 (Reactome) | The efflux pump ABCG2 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). | |||
| REACT_25173 (Reactome) | The potassium-transporting ATPase heterodimer (ATP4A/12A:ATP4B) catalyzes the hydrolysis of ATP coupled with the exchange of H+ and K+ ions across the plasma membrane. It is composed of alpha and beta chains. Two human genes encode the catalytic alpha subunit, ATP4A and ATP12A (Maeda et al, 1990; Grishin et al, 1994). ATP4A is responsible for acid production in the stomach. ATP12A is responsible for potassium absorption in various tissues. One human gene encodes the beta subunit, ATP4B (Ma et al, 1991). | |||
| REACT_25198 (Reactome) | Hephaestin oxidizes ferrous iron after export from duodenal cells to enable its transport via transferrin (Griffiths et al, 2005). | |||
| REACT_25203 (Reactome) | 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). | |||
| REACT_25246 (Reactome) | The 5-hydroxytryptamine receptor (HTR3) family are members of the superfamily of ligand-gated ion channels (LGICs). Five receptors (HTR3A-E) form a heteropentamer. Binding of the neurotransmitter 5-hydroxytryptamine (5HT, serotonin) to the HTR3 complex opens the channel, which in turn, leads to an excitatory response in neurons and is permeable to sodium, potassium, and calcium ions (Miyake et al. 1995, Davies et al. 1999, Niesler et al. 2007). | |||
| REACT_25268 (Reactome) | 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). | |||
| REACT_25277 (Reactome) | When endosomal pH reaches 6,0, protons replace the iron ions in the transferrin/receptor complex (Hemadi et al, 2006). | |||
| REACT_25287 (Reactome) | The sodium/potassium-transporting ATPase (ATP1A:ATP1B:FXYD) is composed of three subunits - alpha (catalytic part), beta and gamma. The trimer catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane, creating the electrochemical gradient which provides energy for the active transport of various nutrients. Four human genes encode the catalytic alpha subunits, ATP1A1-4 (Kawakami et al, 1986; Shull et al, 1989; Ovchinnikov et al, 1988; Keryanov and Gardner, 2002). Defects in ATP1A2 cause alternating hemiplegia of childhood (AHC) (Swoboda et al, 2004). Another defect in ATP1A2 causes familial hemiplegic migraine type 2 (FHM2) (Vanmolkot et al, 2003). Defects in ATP1A3 are the cause of dystonia type 12 (DYT12) (de Carvalho Aguiar et al, 2004). Three human genes encode the non-catalytic beta subunits, ATP1B1-3. The beta subunits are thought to mediate the number of sodium pumps transported to the plasma membrane (Lane et al, 1989; Ruiz et al, 1996; Malik et al, 1996). FXYD proteins belong to a family of small membrane proteins that are auxiliary gamma subunits of Na-K-ATPase. At least six members of this family, FYD1-4, 6 and 7, have been shown to regulate Na-K-ATPase activity (Geering 2006, Choudhury et al. 2007). Defects in FXYD2 are the cause of hypomagnesemia type 2 (HOMG2) (Meij et al, 2000). | |||
| REACT_25301 (Reactome) | Accumulation of calcium into the Golgi apparatus is mediated by sarco(endo)plasmic reticulum calcium-ATPases (SERCAs) and by secretory pathway calcium-ATPases (SPCAs). There are two human genes which encode SPCAs; ATP2C1 and ATP2C2 which encode magnesium-dependent calcium-transporting ATPase type 2C members 1 and 2 (ATP2C1 and 2) respectively (Sudbrak et al, 2000; Vanoevelen et al, 2005). Defects in ATP2C1 are the cause of Hailey-Hailey disease (HHD), an autosomal dominant disease characterized by persistent blisters and erosions of the skin (Hu et al, 2000). | |||
| REACT_25304 (Reactome) | The glycine receptor (GLR) is a ligand-gated ion channel. It is functional as a heteropentamer, consisting of alpha (GLRA) and beta (GLRB) subunits. With no ligand bound, the receptor complex is closed to chloride ions. Binding of the inhibitory neurotransmitter glycine (Gly) to this receptor complex increases chloride conductance into neurons and thus produces hyperpolarization (inhibition of neuronal firing) (Grenningloh et al. 1990, Nikolic et al. 1998, Handford et al. 1996). | |||
| REACT_25316 (Reactome) | Intracellular pools of Ca2+ serve as the source for inositol 1,4,5-trisphosphate (IP3) -induced alterations in cytoplasmic free Ca2+. In most human cells Ca2+ is stored in the lumen of the sarco/endoplastic reticulum by ATPases known as SERCAs (ATP2As). In platelets, ATP2As transport Ca2+ into the platelet dense tubular network. ATP2As are P-type ATPases, similar to the plasma membrane Na+ and Ca+-ATPases. Humans have three genes for SERCA pumps; ATP2A1-3. Studies on ATP2A1 suggest that it binds two Ca2+ ions from the cytoplasm and is subsequently phosphorylated at Asp351 before translocating Ca2+ into the SR lumen. There is a counter transport of two or possibly three protons ensuring partial charge balancing. | |||
| REACT_25385 (Reactome) | Transferrin is the main transporter of iron in the blood. It can take up two ferric iron ions (Wally et al, 2006). | |||
| REACT_25389 (Reactome) | 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). | |||
| REACT_25391 (Reactome) | The GABA(A)-rho receptor (GABRR) is expressed in many areas of the brain, but in contrast to other GABA(A) receptors, has especially high expression in the retina. It is functional as a homopentamer and is permeable to chloride ions when GABA binds to it (Cutting et al. 1991, Cutting et al. 1992, Bailey et al. 1990). | |||
| RYR tetramer
CASQ polymer TRDN junctin | REACT_160216 (Reactome) | |||
| SCNN channels | REACT_160095 (Reactome) | |||
| SCNN channels | REACT_160256 (Reactome) | |||
| SLC11A2 | REACT_20526 (Reactome) | |||
| SLC17A3 | REACT_160084 (Reactome) | |||
| SLC17A3 | REACT_160104 (Reactome) | |||
| SLC46A1 | REACT_25025 (Reactome) | |||
| SLC9B1/C2 | REACT_160312 (Reactome) | |||
| SLC9B2 | REACT_160252 (Reactome) | |||
| SLC9C1 | REACT_160226 (Reactome) | |||
| STEAP3 | REACT_24919 (Reactome) | |||
| TF TFRC dimer | Arrow | REACT_25277 (Reactome) | ||
| TF | Arrow | REACT_24927 (Reactome) | ||
| TFRC dimer | Arrow | REACT_24927 (Reactome) | ||
| TFRC dimer | REACT_24945 (Reactome) | |||
| TF | REACT_25385 (Reactome) | |||
| TPCN1/2 | REACT_160271 (Reactome) | |||
| TTYH1-3 | REACT_160181 (Reactome) | |||
| TTYH2/3 | REACT_160263 (Reactome) | |||
| Ub-SCNN channels | Arrow | REACT_160256 (Reactome) | ||
| Ub | REACT_160256 (Reactome) | |||
| V-ATPase | REACT_25268 (Reactome) | |||
| WNKs | Arrow | REACT_160256 (Reactome) | ||
| amiloride | TBar | REACT_160095 (Reactome) | ||
| amiloride | TBar | REACT_160227 (Reactome) | ||
| e- | REACT_24919 (Reactome) | |||
| e- | REACT_25114 (Reactome) | |||
| heme | Arrow | REACT_25155 (Reactome) | ||
| heme | REACT_22100 (Reactome) | |||
| heme | REACT_25155 (Reactome) | |||
| holoTF | REACT_24945 (Reactome) | |||
| p-S56,S534-N-acetyl-L-alanine-FLVCR1 | REACT_25203 (Reactome) |
