Iron uptake and transport (Homo sapiens)

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35, 39, 434, 33, 5119, 4417, 3818, 412445233, 12, 13, 2226, 2919, 4411103032, 4018, 41364, 33, 518, 14, 20, 342, 2127166, 284637, 4220, 34, 491, 7, 314, 9, 51520, 34, 494831, 5215, 47, 5023cytosolmitochondrial matrixendosome lumenmitochondrial intermembrane spaceFBXL5 LCN2 NADP+ATP6V1B1 ATP6V0A1 ATP6V1C1 ATP6V1G3 ALAD mRNA LCN2:2,5DHBA:Fe3+apoTFLCN2 ATP6V1B2 ATP6V0E1 STEAP3-like proteinsSLC40A1:HEPH:6Cu2+H+ATP6V1E2 ATP6V1B2 IREB2 HFETFR2UBC(609-684) apoTF FTH1 mRNA CYBRD1:HemeFe3+ LCN2 PiATP6V0C Fe3+ ATP6V1C2 ATP6V1A ATP6V0A4 H2OATP6V1E1 heme ATP6V0D2 ACO1, IREB2apoTF ALAD mRNA SKP1TFRC(1-760) UBB(1-76) SLC22A17 Fe(3+)O(OH)FTL mRNA IREB2 CAND1 UBB(77-152) UBC(533-608) ATP6V1A hemeholoTF:TFRC dimerSKP1:FBXL5:CUL1:NEDD8HFE apoTF UBA52(1-76) TCIRG1 ACO1H+ATP6V0D1 ATP6V1F ATP6V1H ACO1 TFRC(1-760) Fe3+ ADPp-S56,S534-N-acetyl-L-alanine-FLVCR1V-ATPase:ATP6AP1H+TFR2 UBC(457-532) RPS27A(1-76) FTMT 24merFeHMCOO2ADP2.5DHBA ATP6V0A1 Ferritin ComplexATP6V1E2 ATP6AP1 H2OACO1:4Fe-4STFRC mRNA UBC(153-228) NEDD8FTL mRNA apoTF ATP6V0D2 ATP6V1C2 STEAP2 Fe3+ATP6V0C 2.5DHBA ATP6AP1ACO1 holoTF:TFRC dimerTFRC mRNA Fe3+ATP6V1D NADPHCu2+ apoTF:TFRC dimerATP6V0A2 ATP6V1G2 V-ATPaseSLC22A17:LCN2:2,5DHBA:Fe3+FeHMFe3+ ATP6V0E2 FBXL5 ATP6V0B CUL1 SLC40A1 CANDI:CUL1ATP6V1C1 UbO2Fe3+TFRC, ALAD, FTL,FTH1 mRNAs2.5DHBA e-SLC40A1 CYBRD1 H2OATP6V1F FTH1 FTMT HEPH HFE:TFRC dimerH+ABCG2 dimerMCOLN1ATP6V1E1 SLC22A17Fe2+ACO1 SLC11A2UBC(1-76) TFRC(1-760) STEAP3 FTH1 mRNA H+UBC(305-380) CUL1 ATP6V1G1 TFRC dimerFTL ATP6V0E2 UBC(381-456) Fe3+ 4Fe-4STFRC(1-760) apoTF HC-ABCG2 H+O2Cu2+ CAND1FBXL54Fe-4S PiTCIRG1 TFRC(1-760) Fe2+ATPNEDD8 HMOX1 hemeapoTF LCN2:2,5DHBASLC46A1IREB2HMOX1,2ATP6V0D1 O2TFRC(1-760) ISCITATP6V1H ATP6V0B SKP1 ATPATP6V0E1 TFR2 dimer:2xholoTFapoTF:TFRC dimerCITFe2+Ub-K-IREB2e-ATP6V1G3 UBB(153-228) ATP6V1D Fe2+UBC(229-304) BVGLRX3H+HMOX2 2.5DHBA holoTFATP6V1G1 CUL1CUL1 ATP6V0A2 UBC(77-152) ATP6V1B1 Fe2+SKP1:CUL1:FBXL5CP SLC40A1:CP:6Cu2+SKP1 Fe(3+)O(OH)Fe3+ LCN2 SLC22A17 ATP6V1G2 SLC22A17:LCN2:2,5DHBAATP6V0A4 H2OACO1, IREB2:TFRC,ALAD, FTL, FTH1mRNAs25


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). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 917937
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Stephan, Ralf

Quality Tags

Ontology Terms

 

Bibliography

View all...
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History

View all...
CompareRevisionActionTimeUserComment
101751view12:32, 5 November 2018EgonwCHEBI:29036 is the identifier for Cu2+
101635view11:49, 1 November 2018ReactomeTeamreactome version 66
101171view21:36, 31 October 2018ReactomeTeamreactome version 65
100697view20:09, 31 October 2018ReactomeTeamreactome version 64
100247view16:54, 31 October 2018ReactomeTeamreactome version 63
99799view15:19, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99349view12:48, 31 October 2018ReactomeTeamreactome version 62
93836view13:39, 16 August 2017ReactomeTeamreactome version 61
93391view11:22, 9 August 2017ReactomeTeamreactome version 61
86958view13:26, 15 July 2016MkutmonOntology Term : 'iron transport pathway' added !
86477view09:19, 11 July 2016ReactomeTeamreactome version 56
83068view09:51, 18 November 2015ReactomeTeamVersion54
81385view12:54, 21 August 2015ReactomeTeamVersion53
76854view08:12, 17 July 2014ReactomeTeamFixed remaining interactions
76559view11:54, 16 July 2014ReactomeTeamFixed remaining interactions
75892view09:54, 11 June 2014ReactomeTeamRe-fixing comment source
75592view10:43, 10 June 2014ReactomeTeamReactome 48 Update
74947view13:47, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74591view08:38, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2.5DHBA MetaboliteCHEBI:17189 (ChEBI)
4Fe-4S R-ALL-5690881 (Reactome)
4Fe-4SR-ALL-5690881 (Reactome)
ABCG2 dimerComplexR-HSA-917863 (Reactome)
ACO1 ProteinP21399 (Uniprot-TrEMBL)
ACO1, IREB2:TFRC,

ALAD, FTL, FTH1

mRNAs
ComplexR-HSA-5690882 (Reactome)
ACO1, IREB2ComplexR-HSA-5690910 (Reactome)
ACO1:4Fe-4SComplexR-HSA-5690885 (Reactome)
ACO1ProteinP21399 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ALAD mRNA ProteinENST00000409155 (Ensembl)
ATP6AP1 ProteinQ15904 (Uniprot-TrEMBL)
ATP6AP1ProteinQ15904 (Uniprot-TrEMBL)
ATP6V0A1 ProteinQ93050 (Uniprot-TrEMBL)
ATP6V0A2 ProteinQ9Y487 (Uniprot-TrEMBL)
ATP6V0A4 ProteinQ9HBG4 (Uniprot-TrEMBL)
ATP6V0B ProteinQ99437 (Uniprot-TrEMBL)
ATP6V0C ProteinP27449 (Uniprot-TrEMBL)
ATP6V0D1 ProteinP61421 (Uniprot-TrEMBL)
ATP6V0D2 ProteinQ8N8Y2 (Uniprot-TrEMBL)
ATP6V0E1 ProteinO15342 (Uniprot-TrEMBL)
ATP6V0E2 ProteinQ8NHE4 (Uniprot-TrEMBL)
ATP6V1A ProteinP38606 (Uniprot-TrEMBL)
ATP6V1B1 ProteinP15313 (Uniprot-TrEMBL)
ATP6V1B2 ProteinP21281 (Uniprot-TrEMBL)
ATP6V1C1 ProteinP21283 (Uniprot-TrEMBL)
ATP6V1C2 ProteinQ8NEY4 (Uniprot-TrEMBL)
ATP6V1D ProteinQ9Y5K8 (Uniprot-TrEMBL)
ATP6V1E1 ProteinP36543 (Uniprot-TrEMBL)
ATP6V1E2 ProteinQ96A05 (Uniprot-TrEMBL)
ATP6V1F ProteinQ16864 (Uniprot-TrEMBL)
ATP6V1G1 ProteinO75348 (Uniprot-TrEMBL)
ATP6V1G2 ProteinO95670 (Uniprot-TrEMBL)
ATP6V1G3 ProteinQ96LB4 (Uniprot-TrEMBL)
ATP6V1H ProteinQ9UI12 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
BVMetaboliteCHEBI:17033 (ChEBI)
CAND1 ProteinQ86VP6 (Uniprot-TrEMBL)
CAND1ProteinQ86VP6 (Uniprot-TrEMBL)
CANDI:CUL1ComplexR-HSA-5691143 (Reactome)
CITMetaboliteCHEBI:30769 (ChEBI)
COMetaboliteCHEBI:17245 (ChEBI)
CP ProteinP00450 (Uniprot-TrEMBL)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
CUL1ProteinQ13616 (Uniprot-TrEMBL)
CYBRD1 ProteinQ53TN4 (Uniprot-TrEMBL)
CYBRD1:HemeComplexR-HSA-917916 (Reactome)
Cu2+ MetaboliteCHEBI:29036 (ChEBI)
FBXL5 ProteinQ9UKA1 (Uniprot-TrEMBL)
FBXL5ProteinQ9UKA1 (Uniprot-TrEMBL)
FTH1 ProteinP02794 (Uniprot-TrEMBL)
FTH1 mRNA ProteinENST00000273550 (Ensembl)
FTL ProteinP02792 (Uniprot-TrEMBL)
FTL mRNA ProteinENST00000331825 (Ensembl)
FTMT 24merComplexR-HSA-5691188 (Reactome)
FTMT ProteinQ8N4E7 (Uniprot-TrEMBL)
Fe(3+)O(OH)MetaboliteCHEBI:78619 (ChEBI)
Fe2+MetaboliteCHEBI:18248 (ChEBI)
Fe3+ MetaboliteCHEBI:29034 (ChEBI)
Fe3+MetaboliteCHEBI:29034 (ChEBI)
FeHMMetaboliteCHEBI:36144 (ChEBI)
Ferritin ComplexComplexR-HSA-434350 (Reactome) 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.
GLRX3ProteinO76003 (Uniprot-TrEMBL)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HC-ABCG2 ProteinQ9UNQ0 (Uniprot-TrEMBL)
HEPH ProteinQ9BQS7 (Uniprot-TrEMBL)
HFE ProteinQ30201 (Uniprot-TrEMBL)
HFE:TFRC dimerComplexR-HSA-5691129 (Reactome)
HFEProteinQ30201 (Uniprot-TrEMBL)
HMOX1 ProteinP09601 (Uniprot-TrEMBL)
HMOX1,2ComplexR-HSA-189382 (Reactome)
HMOX2 ProteinP30519 (Uniprot-TrEMBL)
IREB2 ProteinP48200 (Uniprot-TrEMBL)
IREB2ProteinP48200 (Uniprot-TrEMBL)
ISCITMetaboliteCHEBI:151 (ChEBI)
LCN2 ProteinP80188 (Uniprot-TrEMBL)
LCN2:2,5DHBA:Fe3+ComplexR-HSA-5229238 (Reactome)
LCN2:2,5DHBAComplexR-HSA-5229290 (Reactome)
MCOLN1ProteinQ9GZU1 (Uniprot-TrEMBL)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NEDD8 ProteinQ15843 (Uniprot-TrEMBL)
NEDD8ProteinQ15843 (Uniprot-TrEMBL)
O2MetaboliteCHEBI:15379 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
SKP1:CUL1:FBXL5ComplexR-HSA-5691178 (Reactome)
SKP1:FBXL5:CUL1:NEDD8ComplexR-HSA-5691141 (Reactome)
SKP1ProteinP63208 (Uniprot-TrEMBL)
SLC11A2ProteinP49281 (Uniprot-TrEMBL)
SLC22A17 ProteinQ8WUG5 (Uniprot-TrEMBL)
SLC22A17:LCN2:2,5DHBA:Fe3+ComplexR-HSA-5246491 (Reactome)
SLC22A17:LCN2:2,5DHBAComplexR-HSA-5671708 (Reactome)
SLC22A17ProteinQ8WUG5 (Uniprot-TrEMBL)
SLC40A1 ProteinQ9NP59 (Uniprot-TrEMBL)
SLC40A1:CP:6Cu2+ComplexR-HSA-904825 (Reactome)
SLC40A1:HEPH:6Cu2+ComplexR-HSA-904821 (Reactome)
SLC46A1ProteinQ96NT5 (Uniprot-TrEMBL)
STEAP2 ProteinQ8NFT2 (Uniprot-TrEMBL)
STEAP3 ProteinQ658P3 (Uniprot-TrEMBL)
STEAP3-like proteinsComplexR-HSA-3907278 (Reactome) 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.
TCIRG1 ProteinQ13488 (Uniprot-TrEMBL)
TFR2 ProteinQ9UP52 (Uniprot-TrEMBL)
TFR2 dimer:2xholoTFComplexR-HSA-5691094 (Reactome)
TFR2ProteinQ9UP52 (Uniprot-TrEMBL)
TFRC dimerComplexR-HSA-917784 (Reactome)
TFRC mRNA ProteinENST00000360110 (Ensembl)
TFRC(1-760) ProteinP02786 (Uniprot-TrEMBL)
TFRC, ALAD, FTL, FTH1 mRNAsComplexR-HSA-5690884 (Reactome)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-K-IREB2ProteinP48200 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
V-ATPase:ATP6AP1ComplexR-HSA-5252081 (Reactome)
V-ATPaseComplexR-HSA-912600 (Reactome)
apoTF ProteinP02787 (Uniprot-TrEMBL)
apoTF:TFRC dimerComplexR-HSA-917833 (Reactome)
apoTF:TFRC dimerComplexR-HSA-917912 (Reactome)
apoTFProteinP02787 (Uniprot-TrEMBL)
e-MetaboliteCHEBI:10545 (ChEBI)
heme MetaboliteCHEBI:17627 (ChEBI)
hemeMetaboliteCHEBI:17627 (ChEBI)
holoTF:TFRC dimerComplexR-HSA-917799 (Reactome)
holoTF:TFRC dimerComplexR-HSA-917834 (Reactome)
holoTFComplexR-HSA-917889 (Reactome)
p-S56,S534-N-acetyl-L-alanine-FLVCR1ProteinQ9Y5Y0 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
4Fe-4SR-HSA-5690873 (Reactome)
ABCG2 dimermim-catalysisR-HSA-917979 (Reactome)
ACO1, IREB2:TFRC,

ALAD, FTL, FTH1

mRNAs
ArrowR-HSA-5690886 (Reactome)
ACO1, IREB2R-HSA-5690886 (Reactome)
ACO1:4Fe-4SArrowR-HSA-5690873 (Reactome)
ACO1:4Fe-4Smim-catalysisR-HSA-5690911 (Reactome)
ACO1R-HSA-5690873 (Reactome)
ADPArrowR-HSA-917841 (Reactome)
ADPArrowR-HSA-917979 (Reactome)
ATP6AP1R-HSA-5252133 (Reactome)
ATPR-HSA-917841 (Reactome)
ATPR-HSA-917979 (Reactome)
BVArrowR-HSA-189398 (Reactome)
CAND1R-HSA-5691131 (Reactome)
CANDI:CUL1ArrowR-HSA-5691131 (Reactome)
CITR-HSA-5690911 (Reactome)
COArrowR-HSA-189398 (Reactome)
CUL1R-HSA-5691131 (Reactome)
CUL1R-HSA-5691167 (Reactome)
CYBRD1:Hememim-catalysisR-HSA-917805 (Reactome)
FBXL5R-HSA-5691167 (Reactome)
FTMT 24mermim-catalysisR-HSA-5691107 (Reactome)
Fe(3+)O(OH)ArrowR-HSA-1562626 (Reactome)
Fe(3+)O(OH)ArrowR-HSA-5691107 (Reactome)
Fe2+ArrowR-HSA-189398 (Reactome)
Fe2+ArrowR-HSA-435349 (Reactome)
Fe2+ArrowR-HSA-442368 (Reactome)
Fe2+ArrowR-HSA-904830 (Reactome)
Fe2+ArrowR-HSA-917805 (Reactome)
Fe2+ArrowR-HSA-917811 (Reactome)
Fe2+ArrowR-HSA-917936 (Reactome)
Fe2+R-HSA-1562626 (Reactome)
Fe2+R-HSA-435349 (Reactome)
Fe2+R-HSA-442368 (Reactome)
Fe2+R-HSA-5691107 (Reactome)
Fe2+R-HSA-904830 (Reactome)
Fe2+R-HSA-917891 (Reactome)
Fe2+R-HSA-917933 (Reactome)
Fe2+R-HSA-917936 (Reactome)
Fe3+ArrowR-HSA-5671707 (Reactome)
Fe3+ArrowR-HSA-917835 (Reactome)
Fe3+ArrowR-HSA-917891 (Reactome)
Fe3+ArrowR-HSA-917933 (Reactome)
Fe3+R-HSA-5229273 (Reactome)
Fe3+R-HSA-917805 (Reactome)
Fe3+R-HSA-917811 (Reactome)
Fe3+R-HSA-917888 (Reactome)
FeHMArrowR-HSA-917870 (Reactome)
FeHMR-HSA-917870 (Reactome)
Ferritin Complexmim-catalysisR-HSA-1562626 (Reactome)
GLRX3TBarR-HSA-5690886 (Reactome)
H+ArrowR-HSA-435349 (Reactome)
H+ArrowR-HSA-917841 (Reactome)
H+R-HSA-1562626 (Reactome)
H+R-HSA-435349 (Reactome)
H+R-HSA-5691107 (Reactome)
H+R-HSA-917841 (Reactome)
H+R-HSA-917891 (Reactome)
H+R-HSA-917933 (Reactome)
H2OArrowR-HSA-189398 (Reactome)
H2OArrowR-HSA-917891 (Reactome)
H2OArrowR-HSA-917933 (Reactome)
H2OR-HSA-917841 (Reactome)
H2OR-HSA-917979 (Reactome)
HFE:TFRC dimerArrowR-HSA-5691154 (Reactome)
HFER-HSA-5691154 (Reactome)
HMOX1,2mim-catalysisR-HSA-189398 (Reactome)
IREB2R-HSA-5691108 (Reactome)
ISCITArrowR-HSA-5690911 (Reactome)
LCN2:2,5DHBA:Fe3+ArrowR-HSA-5229273 (Reactome)
LCN2:2,5DHBA:Fe3+R-HSA-5246444 (Reactome)
LCN2:2,5DHBAR-HSA-5229273 (Reactome)
MCOLN1mim-catalysisR-HSA-917936 (Reactome)
NADP+ArrowR-HSA-189398 (Reactome)
NADPHR-HSA-189398 (Reactome)
NEDD8R-HSA-5691176 (Reactome)
O2R-HSA-1562626 (Reactome)
O2R-HSA-189398 (Reactome)
O2R-HSA-5691107 (Reactome)
O2R-HSA-917891 (Reactome)
O2R-HSA-917933 (Reactome)
PiArrowR-HSA-917841 (Reactome)
PiArrowR-HSA-917979 (Reactome)
R-HSA-1562626 (Reactome) 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).
R-HSA-189398 (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.
R-HSA-435349 (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). 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).
R-HSA-442368 (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 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.
R-HSA-5229273 (Reactome) 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).
R-HSA-5246444 (Reactome) 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).
R-HSA-5252133 (Reactome) 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).
R-HSA-5671707 (Reactome) 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).
R-HSA-5690873 (Reactome) 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).
R-HSA-5690886 (Reactome) 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).
R-HSA-5690911 (Reactome) 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).
R-HSA-5691107 (Reactome) 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).
R-HSA-5691108 (Reactome) 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.
R-HSA-5691131 (Reactome) 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).
R-HSA-5691150 (Reactome) 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).
R-HSA-5691154 (Reactome) 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).
R-HSA-5691167 (Reactome) 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.
R-HSA-5691176 (Reactome) 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).
R-HSA-904830 (Reactome) 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.
R-HSA-917805 (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).
R-HSA-917807 (Reactome) The transferrin/receptor complex is internalized as a clathrin-coated vesicle (Willingham et al, 1984; Harding et al, 1983).
R-HSA-917811 (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).
R-HSA-917814 (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).
R-HSA-917835 (Reactome) When endosomal pH reaches 6,0, protons replace the iron ions in the transferrin/receptor complex (Hemadi et al, 2006).
R-HSA-917839 (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).
R-HSA-917841 (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).
R-HSA-917870 (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).
R-HSA-917888 (Reactome) 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).
R-HSA-917891 (Reactome) 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).
R-HSA-917892 (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).
R-HSA-917933 (Reactome) Hephaestin oxidizes ferrous iron (Fe2+) to ferric iron (Fe3+) after export from duodenal cells to enable its transport via transferrin (Griffiths et al, 2005).
R-HSA-917936 (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).
R-HSA-917979 (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).
R-HSA-917987 (Reactome) 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).
SKP1:CUL1:FBXL5ArrowR-HSA-5691167 (Reactome)
SKP1:CUL1:FBXL5R-HSA-5691176 (Reactome)
SKP1:FBXL5:CUL1:NEDD8ArrowR-HSA-5691176 (Reactome)
SKP1:FBXL5:CUL1:NEDD8mim-catalysisR-HSA-5691108 (Reactome)
SKP1R-HSA-5691167 (Reactome)
SLC11A2mim-catalysisR-HSA-435349 (Reactome)
SLC22A17:LCN2:2,5DHBA:Fe3+ArrowR-HSA-5246444 (Reactome)
SLC22A17:LCN2:2,5DHBA:Fe3+R-HSA-5671707 (Reactome)
SLC22A17:LCN2:2,5DHBAArrowR-HSA-5671707 (Reactome)
SLC22A17R-HSA-5246444 (Reactome)
SLC22A17mim-catalysisR-HSA-5671707 (Reactome)
SLC40A1:CP:6Cu2+mim-catalysisR-HSA-904830 (Reactome)
SLC40A1:CP:6Cu2+mim-catalysisR-HSA-917891 (Reactome)
SLC40A1:HEPH:6Cu2+mim-catalysisR-HSA-442368 (Reactome)
SLC40A1:HEPH:6Cu2+mim-catalysisR-HSA-917933 (Reactome)
SLC46A1mim-catalysisR-HSA-917870 (Reactome)
STEAP3-like proteinsmim-catalysisR-HSA-917811 (Reactome)
TFR2 dimer:2xholoTFArrowR-HSA-5691150 (Reactome)
TFR2R-HSA-5691150 (Reactome)
TFRC dimerArrowR-HSA-917839 (Reactome)
TFRC dimerR-HSA-5691154 (Reactome)
TFRC dimerR-HSA-917987 (Reactome)
TFRC, ALAD, FTL, FTH1 mRNAsR-HSA-5690886 (Reactome)
Ub-K-IREB2ArrowR-HSA-5691108 (Reactome)
UbR-HSA-5691108 (Reactome)
V-ATPase:ATP6AP1ArrowR-HSA-5252133 (Reactome)
V-ATPase:ATP6AP1mim-catalysisR-HSA-917841 (Reactome)
V-ATPaseR-HSA-5252133 (Reactome)
apoTF:TFRC dimerArrowR-HSA-917814 (Reactome)
apoTF:TFRC dimerArrowR-HSA-917835 (Reactome)
apoTF:TFRC dimerR-HSA-917814 (Reactome)
apoTF:TFRC dimerR-HSA-917839 (Reactome)
apoTFArrowR-HSA-917839 (Reactome)
apoTFR-HSA-917888 (Reactome)
e-R-HSA-917805 (Reactome)
e-R-HSA-917811 (Reactome)
hemeArrowR-HSA-917892 (Reactome)
hemeArrowR-HSA-917979 (Reactome)
hemeR-HSA-189398 (Reactome)
hemeR-HSA-917892 (Reactome)
hemeR-HSA-917979 (Reactome)
holoTF:TFRC dimerArrowR-HSA-917807 (Reactome)
holoTF:TFRC dimerArrowR-HSA-917987 (Reactome)
holoTF:TFRC dimerR-HSA-917807 (Reactome)
holoTF:TFRC dimerR-HSA-917835 (Reactome)
holoTFArrowR-HSA-917888 (Reactome)
holoTFR-HSA-5691150 (Reactome)
holoTFR-HSA-917987 (Reactome)
p-S56,S534-N-acetyl-L-alanine-FLVCR1mim-catalysisR-HSA-917892 (Reactome)
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