Iron uptake and transport (Homo sapiens)

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25, 80, 16716027, 17632, 10031, 607, 19, 57, 64, 86...35, 4415, 41, 59, 78, 10917771, 89, 10477, 1489, 43, 134112, 1461088, 11810333, 152, 17346, 12852, 74, 110, 141, 15428, 73, 94, 98, 106...243948, 61, 114, 1711, 30, 56, 63, 133...10883, 161268271, 89, 10417, 18, 159, 1691077, 14838, 9021, 23, 9740, 8455, 127, 14314, 1446212, 9670, 123, 13921, 16614567, 131, 13667522, 65, 91, 105, 126...3, 11, 47, 69, 93...516, 20, 29, 49, 95...40, 76, 841772, 42, 79, 15358, 81, 8517099, 11613, 53, 17572112, 14636, 45, 50125, 1304, 8, 37, 51, 66...12211768, 71, 10454, 102, 142late endosome lumenmitochondrial intermembrane spaceendosome lumenmitochondrial matrixGolgi lumencytosolsarcoplasmic reticulum lumenlysosomal lumenplatelet dense tubular network lumensperm flagellumendoplasmic reticulum lumenHMOX1,2amilorideHTR3 pentamer:5HTGLRB SCNN1D Ca2+LCN2 ATP13A1ATP8A2 GABRA3 BEST4 TTYH2 Ca2+ATP11A GABRB3 ATP2C1 UbCl-BEST1 TRPV6 WNK2 Ca2+HEPH GABRB2 TRPC3(1-848) GABA ATP8B3 BEST3 ATPCLCN5 SLC9B1 CLCA4 (?-919) ATP1A3 TFRC(1-760) Fe3+UBB(1-76) UBC(609-684) Na+BSND ATP13A4 FeHMH+TTYH3 ATP2B2 ATPNALCN ATP2A1 p-T357,S358-MLKL oligomer UBC(77-152) HTR3C Cl-Ub-SCNN channelsPiHCO3-PLN pentamerCLCA3P CLCAsFXYD1 ATP1A2 STEAP3 ASIC2 H+cationCu2+PiCl-ATP6V0A4 ATP6V1E1 2.5DHBA BVCLCN7:OSTM1ATP2A1-3apoTF FXYD4 ATP1B3 ATP2A2 NEDD4L ATP2A3 TTYH1-3ATP8B1 H+ATP13A2Na+/Li+CLCN2 RAF1:SGK:TSC22D3:WPPGLRA2 ADPCa2+SGK1 ATP11C H2OUBC(153-228) FXYD2 ATPNa+SLC17A3(1-498)GABRB1 SLC9B1/C2ATPCu2+apoTF RYR1 CLCA2 (?-943) MCOLN1 ATP2B1-4TRPV2 ATP12A UBC(305-380) CLCN1/2/KA/KBMCOLN3 Na+ CASQ2 polymer TPCN1 ATP2B1 ATP7A TFRC(1-760) NADPHATP6V0E2 ATP6V1G2 Fe2+CUTC H+ Cu2+ATP2C1/2:Mg2+TRDN H+ATP6V0A4 TRPV5 ATP4A PDZD11 2.5DHBA CLCN6 ATP6V0E2 TRPsNSAIDFXYD3 O2K+O2Li+ hemeATP6V0C UBC(229-304) N-terminus CLCAsTCIRG1 Ca2+TRPC1 ATP4B Pip-S-RIPK1:p-S199,227-RIPK3:p-T357,S358-MLKL oligomerTRPC7 SLC9C2 NADP+H2OATP6V1G3 ATP6V1E2 ANO6 ATP6V0B heme H+GLRA4 CLCA1 (22-?) ABCG2 dimerATPCl-CYBRD1 K+FKBP1B Ca2+GLRA3 GABRR pentamer:GABASCNN channelshemeATP6V1D TRPM5 TRPC5 PiMg2+ PS SLC40A1 divalent metalcationPE CUTC tetramerCUTC APLsp-S56,S534-N-acetyl-L-alanine-FLVCR1ATP1A1 Ca2+K+ATP6V1E2 RYR3 CLCA1 ATPFXYD6 H2OPiATP8B2 GABRG2 Ca2+PiSLC46A1holoTF:TFRC dimerTRPM4,5RYRtetramer:FKBP1Btetramer:CASQpolymer:TRDN:junctinASPH ATP6V0A2 ATPPS Fe2+H+H+GABRA1 SLC17A3OSTM1 Na+urateANO5 ADPGly e-ASIC4GABA UBB(77-152) GABRA2 Ub-SCNN1G ATPGABRR2 BEST2 ATP8A1 APLsTRPM4 Fe3+ UBB(153-228) SLC22A17 P-type ATPases typeIVATP8B4 ATP6V1B2 SLC22A17Na+ ATP6AP1 TCIRG1 FTH1 ATP6V1H UBC(533-608) ATP6V1D ANO4 H2OSLC40A1 TRPM3 GABRR3 Na+Na+p-S-RIPK1:p-S199,227-RIPK3 oligomer WNKsCl-ARHGEF9 ATP6V1E1 GABRR1 PiPE Na+ADPNa+H2OATP1A:ATP1B:FXYDCu2+ ATP6V0C TFRC(1-760) TFRC(1-760) ATP10B Ca2+H2OFe3+ Ca2+Cl-H+p-S16-PLN pentamerH+ANO8 GABRA5 PiTRPM7 SCNN1D UBC(1-76) TRPM8 H2OATP13A4, 5CLCA4 (22-?) ASIC1 ATP6V0D1 CLCN7 CLIC2ATP6V1F ATP6V0B TRPM2 ATP6V0A1 Na+/Li+STEAP2 ATP2A1 H+HC-ABCG2 TRPC4AP divalent metalcationTSC22D3 TRPM1 LCN2 TTYH2/3ATPPiNa+Cu1+UNC79 LCN2 Fe3+ e-Ca2+SGK3 K+ATP2A1-3ATP6V1C2 Cu1+ ATP6V1A ANO10 ATP10A ATP6V1B1 ATP7BFe3+ ADPH2OH+TFRC dimerNa+TRPV1 ATP6V0A2 holoTF2.5DHBA LCN2:2,5DHBATRPC6 PiCa2+SCNN1B H+PiLi+ apoTF SLC40A1:CP:6Cu2+SGK2 ATP6V0D1 H+ATPCl-ADPSLC22A17 Ca2+WNK3 SCNN1A 5HT SLC9C1UNC80 apoTF BESTsNa+Mn2+SLC22A17:LCN2:2,5DHBAATP2B4 ASIC trimer:H+WWP1 WNK1 ANO1 SCNN1B CLCN3ADPATP6V1G2 GLRA:GLRB:GlyholoTF:TFRC dimerTRPV3 MTP1:HEPH:6Cu2+H+TRPC4 ATP6V1B2 HMOX1 ATP13A5 Na+CLCA3P (?-262) Na+MCOLN1Fe3+apoTF:TFRC dimerANO3 NAADPATP6V1G3 TRPV4 ATP6V0D2 PiCa2+Ca2+ATP10D LCN2:2,5DHBA:Fe3+H+ATP2A2 V-ATPaseTPCN1/2COapoTF CLCA3P (21-?) p-S16-PLN Fe2+Fe(3+)O(OH)ATP6V0E1 Ferritin ComplexATP6V1C1 ANO7 apoTF:TFRC dimerCLCA1 (?-914) FTL STEAP3-like proteinsATP6V0D2 HTR3A GABRG3 Na+Na+CASQ1 polymer C-terminus CLCAsWNK4 ATP2B3 ATP6V1B1 ATP6V1F CP ATP2C2 HMOX2 SLC11A2Ub-SCNN1A V-ATPase:ATP6AP1ATP9A ATPCUTC:4xCu+Fe2+H2OSCNN1G ATP7A:PDZD11RAF1 ANO2 GABRheteropentamers:GABAGABRA6 ANO9 NALCN:UNC79:UNC80CLCA2 H+H+UBC(381-456) ATP6V1G1 O2H2OFXYD7 apoTFCa2+CLCA2 (32-?) H2OcationH+TFRC(1-760) urateNa+ATP6AP1ATP6V1C1 ATP4A/12A:ATP4BADPPLN CLCN4/5/6RYR2 ATP9B SRIADPCl-UBC(457-532) CLCA4 ATP6V1H Fe3+ H+ANOsTRPM6 HTR3D CLCNKA GLRA1 Cl-ATP6V1C2 Cu2+ ATP6V1A LCN2 Na+ADPH+ATP1B2 RPS27A(1-76) GABRA4 Fe3+ATP1A4 Ca2+ASIC3 H+CYBRD1:Heme2.5DHBA UBA52(1-76) ATP6V0A1 MCOLN2 H+HTR3B PiATP11B ASIC5 GABRQ TPCN2 ATP1B1 TRPA1 H2OCl-ADPFeHMHCO3-ATPSLC22A17:LCN2:2,5DHBA:Fe3+ATP6V1G1 H2OCLCN4 SLC9B2ADPFe3+CLCNKB HTR3E CLCN1 Mn2+ATP2A3 ATP6V0E1 12134121


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.

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Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
115078view17:02, 25 January 2021ReactomeTeamReactome version 75
113520view11:59, 2 November 2020ReactomeTeamReactome version 74
112719view16:12, 9 October 2020ReactomeTeamReactome version 73
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)
5HT MetaboliteCHEBI:28790 (ChEBI)
ABCG2 dimerComplexR-HSA-917863 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ANO1 ProteinQ5XXA6 (Uniprot-TrEMBL)
ANO10 ProteinQ9NW15 (Uniprot-TrEMBL)
ANO2 ProteinQ9NQ90 (Uniprot-TrEMBL)
ANO3 ProteinQ9BYT9 (Uniprot-TrEMBL)
ANO4 ProteinQ32M45 (Uniprot-TrEMBL)
ANO5 ProteinQ75V66 (Uniprot-TrEMBL)
ANO6 ProteinQ4KMQ2 (Uniprot-TrEMBL)
ANO7 ProteinQ6IWH7 (Uniprot-TrEMBL)
ANO8 ProteinQ9HCE9 (Uniprot-TrEMBL)
ANO9 ProteinA1A5B4 (Uniprot-TrEMBL)
ANOsComplexR-HSA-2684894 (Reactome)
APLsComplexR-HSA-R-ALL-947588 (Reactome)
APLsComplexR-HSA-R-ALL-947594 (Reactome)
ARHGEF9 ProteinO43307 (Uniprot-TrEMBL)
ASIC trimer:H+ComplexR-HSA-2671886 (Reactome)
ASIC1 ProteinP78348 (Uniprot-TrEMBL)
ASIC2 ProteinQ16515 (Uniprot-TrEMBL)
ASIC3 ProteinQ9UHC3 (Uniprot-TrEMBL)
ASIC4ProteinQ96FT7 (Uniprot-TrEMBL)
ASIC5 ProteinQ9NY37 (Uniprot-TrEMBL)
ASPH ProteinQ12797 (Uniprot-TrEMBL)
ATP10A ProteinO60312 (Uniprot-TrEMBL)
ATP10B ProteinO94823 (Uniprot-TrEMBL)
ATP10D ProteinQ9P241 (Uniprot-TrEMBL)
ATP11A ProteinP98196 (Uniprot-TrEMBL)
ATP11B ProteinQ9Y2G3 (Uniprot-TrEMBL)
ATP11C ProteinQ8NB49 (Uniprot-TrEMBL)
ATP12A ProteinP54707 (Uniprot-TrEMBL)
ATP13A1ProteinQ9HD20 (Uniprot-TrEMBL)
ATP13A2ProteinQ9NQ11 (Uniprot-TrEMBL)
ATP13A4 ProteinQ4VNC1 (Uniprot-TrEMBL)
ATP13A4, 5ComplexR-HSA-5252043 (Reactome)
ATP13A5 ProteinQ4VNC0 (Uniprot-TrEMBL)
ATP1A1 ProteinP05023 (Uniprot-TrEMBL)
ATP1A2 ProteinP50993 (Uniprot-TrEMBL)
ATP1A3 ProteinP13637 (Uniprot-TrEMBL)
ATP1A4 ProteinQ13733 (Uniprot-TrEMBL)
ATP1A:ATP1B:FXYDComplexR-HSA-936770 (Reactome)
ATP1B1 ProteinP05026 (Uniprot-TrEMBL)
ATP1B2 ProteinP14415 (Uniprot-TrEMBL)
ATP1B3 ProteinP54709 (Uniprot-TrEMBL)
ATP2A1 ProteinO14983 (Uniprot-TrEMBL)
ATP2A1-3ComplexR-HSA-418312 (Reactome)
ATP2A1-3ComplexR-HSA-427905 (Reactome)
ATP2A2 ProteinP16615 (Uniprot-TrEMBL)
ATP2A3 ProteinQ93084 (Uniprot-TrEMBL)
ATP2B1 ProteinP20020 (Uniprot-TrEMBL)
ATP2B1-4ComplexR-HSA-418306 (Reactome)
ATP2B2 ProteinQ01814 (Uniprot-TrEMBL)
ATP2B3 ProteinQ16720 (Uniprot-TrEMBL)
ATP2B4 ProteinP23634 (Uniprot-TrEMBL)
ATP2C1 ProteinP98194 (Uniprot-TrEMBL)
ATP2C1/2:Mg2+ComplexR-HSA-936921 (Reactome)
ATP2C2 ProteinO75185 (Uniprot-TrEMBL)
ATP4A ProteinP20648 (Uniprot-TrEMBL)
ATP4A/12A:ATP4BComplexR-HSA-937301 (Reactome)
ATP4B ProteinP51164 (Uniprot-TrEMBL)
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)
ATP7A ProteinQ04656 (Uniprot-TrEMBL)
ATP7A:PDZD11ComplexR-HSA-5358995 (Reactome)
ATP7BProteinP35670 (Uniprot-TrEMBL)
ATP8A1 ProteinQ9Y2Q0 (Uniprot-TrEMBL)
ATP8A2 ProteinQ9NTI2 (Uniprot-TrEMBL)
ATP8B1 ProteinO43520 (Uniprot-TrEMBL)
ATP8B2 ProteinP98198 (Uniprot-TrEMBL)
ATP8B3 ProteinO60423 (Uniprot-TrEMBL)
ATP8B4 ProteinQ8TF62 (Uniprot-TrEMBL)
ATP9A ProteinO75110 (Uniprot-TrEMBL)
ATP9B ProteinO43861 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
BEST1 ProteinO76090 (Uniprot-TrEMBL)
BEST2 ProteinQ8NFU1 (Uniprot-TrEMBL)
BEST3 ProteinQ8N1M1 (Uniprot-TrEMBL)
BEST4 ProteinQ8NFU0 (Uniprot-TrEMBL)
BESTsComplexR-HSA-2744364 (Reactome)
BSND ProteinQ8WZ55 (Uniprot-TrEMBL)
BVMetaboliteCHEBI:17033 (ChEBI)
C-terminus CLCAsComplexR-HSA-5333737 (Reactome)
CASQ1 polymer R-HSA-2855198 (Reactome)
CASQ2 polymer R-HSA-2855188 (Reactome)
CLCA1 (22-?) ProteinA8K7I4 (Uniprot-TrEMBL)
CLCA1 (?-914) ProteinA8K7I4 (Uniprot-TrEMBL)
CLCA1 ProteinA8K7I4 (Uniprot-TrEMBL)
CLCA2 (32-?) ProteinQ9UQC9 (Uniprot-TrEMBL)
CLCA2 (?-943) ProteinQ9UQC9 (Uniprot-TrEMBL)
CLCA2 ProteinQ9UQC9 (Uniprot-TrEMBL)
CLCA3P (21-?) ProteinQ9Y6N3 (Uniprot-TrEMBL)
CLCA3P (?-262) ProteinQ9Y6N3 (Uniprot-TrEMBL)
CLCA3P ProteinQ9Y6N3 (Uniprot-TrEMBL)
CLCA4 (22-?) ProteinQ14CN2 (Uniprot-TrEMBL)
CLCA4 (?-919) ProteinQ14CN2 (Uniprot-TrEMBL)
CLCA4 ProteinQ14CN2 (Uniprot-TrEMBL)
CLCAsComplexR-HSA-5333763 (Reactome)
CLCN1 ProteinP35523 (Uniprot-TrEMBL)
CLCN1/2/KA/KBComplexR-HSA-2744251 (Reactome)
CLCN2 ProteinP51788 (Uniprot-TrEMBL)
CLCN3ProteinP51790 (Uniprot-TrEMBL)
CLCN4 ProteinP51793 (Uniprot-TrEMBL)
CLCN4/5/6ComplexR-HSA-2730688 (Reactome)
CLCN5 ProteinP51795 (Uniprot-TrEMBL)
CLCN6 ProteinP51797 (Uniprot-TrEMBL)
CLCN7 ProteinP51798 (Uniprot-TrEMBL)
CLCN7:OSTM1ComplexR-HSA-2730964 (Reactome)
CLCNKA ProteinP51800 (Uniprot-TrEMBL)
CLCNKB ProteinP51801 (Uniprot-TrEMBL)
CLIC2ProteinO15247 (Uniprot-TrEMBL)
COMetaboliteCHEBI:17245 (ChEBI)
CP ProteinP00450 (Uniprot-TrEMBL)
CUTC ProteinQ9NTM9 (Uniprot-TrEMBL)
CUTC tetramerComplexR-HSA-5334801 (Reactome)
CUTC:4xCu+ComplexR-HSA-5336194 (Reactome)
CYBRD1 ProteinQ53TN4 (Uniprot-TrEMBL)
CYBRD1:HemeComplexR-HSA-917916 (Reactome)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Cl-MetaboliteCHEBI:17996 (ChEBI)
Cu1+ MetaboliteCHEBI:49552 (ChEBI)
Cu1+MetaboliteCHEBI:49552 (ChEBI)
Cu2+ MetaboliteCHEBI:28694 (ChEBI)
Cu2+ MetaboliteCHEBI:29036 (ChEBI)
Cu2+MetaboliteCHEBI:29036 (ChEBI)
FKBP1B ProteinP68106 (Uniprot-TrEMBL)
FTH1 ProteinP02794 (Uniprot-TrEMBL)
FTL ProteinP02792 (Uniprot-TrEMBL)
FXYD1 ProteinO00168 (Uniprot-TrEMBL)
FXYD2 ProteinP54710 (Uniprot-TrEMBL)
FXYD3 ProteinQ14802 (Uniprot-TrEMBL)
FXYD4 ProteinP59646 (Uniprot-TrEMBL)
FXYD6 ProteinQ9H0Q3 (Uniprot-TrEMBL)
FXYD7 ProteinP58549 (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.
GABA MetaboliteCHEBI:16865 (ChEBI)
GABR heteropentamers:GABAComplexR-HSA-975268 (Reactome)
GABRA1 ProteinP14867 (Uniprot-TrEMBL)
GABRA2 ProteinP47869 (Uniprot-TrEMBL)
GABRA3 ProteinP34903 (Uniprot-TrEMBL)
GABRA4 ProteinP48169 (Uniprot-TrEMBL)
GABRA5 ProteinP31644 (Uniprot-TrEMBL)
GABRA6 ProteinQ16445 (Uniprot-TrEMBL)
GABRB1 ProteinP18505 (Uniprot-TrEMBL)
GABRB2 ProteinP47870 (Uniprot-TrEMBL)
GABRB3 ProteinP28472 (Uniprot-TrEMBL)
GABRG2 ProteinP18507 (Uniprot-TrEMBL)
GABRG3 ProteinQ99928 (Uniprot-TrEMBL)
GABRQ ProteinQ9UN88 (Uniprot-TrEMBL)
GABRR pentamer:GABAComplexR-HSA-975448 (Reactome)
GABRR1 ProteinP24046 (Uniprot-TrEMBL)
GABRR2 ProteinP28476 (Uniprot-TrEMBL)
GABRR3 ProteinA8MPY1 (Uniprot-TrEMBL)
GLRA1 ProteinP23415 (Uniprot-TrEMBL)
GLRA2 ProteinP23416 (Uniprot-TrEMBL)
GLRA3 ProteinO75311 (Uniprot-TrEMBL)
GLRA4 ProteinQ5JXX5 (Uniprot-TrEMBL)
GLRA:GLRB:GlyComplexR-HSA-975385 (Reactome)
GLRB ProteinP48167 (Uniprot-TrEMBL)
Gly MetaboliteCHEBI:15428 (ChEBI)
H+ MetaboliteCHEBI:15378 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HC-ABCG2 ProteinQ9UNQ0 (Uniprot-TrEMBL)
HCO3-MetaboliteCHEBI:17544 (ChEBI)
HEPH ProteinQ9BQS7 (Uniprot-TrEMBL)
HMOX1 ProteinP09601 (Uniprot-TrEMBL)
HMOX1,2ComplexR-HSA-189382 (Reactome)
HMOX2 ProteinP30519 (Uniprot-TrEMBL)
HTR3 pentamer:5HTComplexR-HSA-975348 (Reactome)
HTR3A ProteinP46098 (Uniprot-TrEMBL)
HTR3B ProteinO95264 (Uniprot-TrEMBL)
HTR3C ProteinQ8WXA8 (Uniprot-TrEMBL)
HTR3D ProteinQ70Z44 (Uniprot-TrEMBL)
HTR3E ProteinA5X5Y0 (Uniprot-TrEMBL)
K+MetaboliteCHEBI:29103 (ChEBI)
LCN2 ProteinP80188 (Uniprot-TrEMBL)
LCN2:2,5DHBA:Fe3+ComplexR-HSA-5229238 (Reactome)
LCN2:2,5DHBAComplexR-HSA-5229290 (Reactome)
Li+ MetaboliteCHEBI:49713 (ChEBI)
MCOLN1 ProteinQ9GZU1 (Uniprot-TrEMBL)
MCOLN1ProteinQ9GZU1 (Uniprot-TrEMBL)
MCOLN2 ProteinQ8IZK6 (Uniprot-TrEMBL)
MCOLN3 ProteinQ8TDD5 (Uniprot-TrEMBL)
MTP1:HEPH:6Cu2+ComplexR-HSA-904821 (Reactome)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
Mn2+MetaboliteCHEBI:29035 (ChEBI)
N-terminus CLCAsComplexR-HSA-5333722 (Reactome)
NAADPMetaboliteCHEBI:76072 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NALCN ProteinQ8IZF0 (Uniprot-TrEMBL)
NALCN:UNC79:UNC80ComplexR-HSA-2730669 (Reactome)
NEDD4L ProteinQ96PU5 (Uniprot-TrEMBL)
NSAIDMetaboliteCHEBI:35475 (ChEBI)
Na+ MetaboliteCHEBI:29101 (ChEBI)
Na+/Li+ComplexR-HSA-R-ALL-2889062 (Reactome)
Na+/Li+ComplexR-HSA-R-ALL-2889081 (Reactome)
Na+MetaboliteCHEBI:29101 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
OSTM1 ProteinQ86WC4 (Uniprot-TrEMBL)
P-type ATPases type IVComplexR-HSA-939735 (Reactome)
PDZD11 ProteinQ5EBL8 (Uniprot-TrEMBL)
PE MetaboliteCHEBI:16038 (ChEBI)
PLN ProteinP26678 (Uniprot-TrEMBL)
PLN pentamerComplexR-HSA-5578811 (Reactome)
PS MetaboliteCHEBI:18303 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
RAF1 ProteinP04049 (Uniprot-TrEMBL)
RAF1:SGK:TSC22D3:WPPComplexR-HSA-2682342 (Reactome)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
RYR

tetramer:FKBP1B tetramer:CASQ

polymer:TRDN:junctin		ComplexR-HSA-2855167 (Reactome)
RYR1 ProteinP21817 (Uniprot-TrEMBL)
RYR2 ProteinQ92736 (Uniprot-TrEMBL)
RYR3 ProteinQ15413 (Uniprot-TrEMBL)
SCNN channelsComplexR-HSA-2672342 (Reactome)
SCNN1A ProteinP37088 (Uniprot-TrEMBL)
SCNN1B ProteinP51168 (Uniprot-TrEMBL)
SCNN1D ProteinP51172 (Uniprot-TrEMBL)
SCNN1G ProteinP51170 (Uniprot-TrEMBL)
SGK1 ProteinO00141 (Uniprot-TrEMBL)
SGK2 ProteinQ9HBY8 (Uniprot-TrEMBL)
SGK3 ProteinQ96BR1 (Uniprot-TrEMBL)
SLC11A2ProteinP49281 (Uniprot-TrEMBL)
SLC17A3(1-498)ProteinO00476 (Uniprot-TrEMBL)
SLC17A3ProteinO00476 (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)
SLC46A1ProteinQ96NT5 (Uniprot-TrEMBL)
SLC9B1 ProteinQ4ZJI4 (Uniprot-TrEMBL)
SLC9B1/C2ComplexR-HSA-2889056 (Reactome)
SLC9B2ProteinQ86UD5 (Uniprot-TrEMBL)
SLC9C1ProteinQ4G0N8 (Uniprot-TrEMBL)
SLC9C2 ProteinQ5TAH2 (Uniprot-TrEMBL)
SRIProteinP30626 (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)
TFRC dimerComplexR-HSA-917784 (Reactome)
TFRC(1-760) ProteinP02786 (Uniprot-TrEMBL)
TPCN1 ProteinQ9ULQ1 (Uniprot-TrEMBL)
TPCN1/2ComplexR-HSA-2685517 (Reactome)
TPCN2 ProteinQ8NHX9 (Uniprot-TrEMBL)
TRDN ProteinQ13061 (Uniprot-TrEMBL)
TRPA1 ProteinO75762 (Uniprot-TrEMBL)
TRPC1 ProteinP48995 (Uniprot-TrEMBL)
TRPC3(1-848) ProteinQ13507 (Uniprot-TrEMBL)
TRPC4 ProteinQ9UBN4 (Uniprot-TrEMBL)
TRPC4AP ProteinQ8TEL6 (Uniprot-TrEMBL)
TRPC5 ProteinQ9UL62 (Uniprot-TrEMBL)
TRPC6 ProteinQ9Y210 (Uniprot-TrEMBL)
TRPC7 ProteinQ9HCX4 (Uniprot-TrEMBL)
TRPM1 ProteinQ7Z4N2 (Uniprot-TrEMBL)
TRPM2 ProteinO94759 (Uniprot-TrEMBL)
TRPM3 ProteinQ9HCF6 (Uniprot-TrEMBL)
TRPM4 ProteinQ8TD43 (Uniprot-TrEMBL)
TRPM4,5ComplexR-HSA-3295585 (Reactome)
TRPM5 ProteinQ9NZQ8 (Uniprot-TrEMBL)
TRPM6 ProteinQ9BX84 (Uniprot-TrEMBL)
TRPM7 ProteinQ96QT4 (Uniprot-TrEMBL)
TRPM8 ProteinQ7Z2W7 (Uniprot-TrEMBL)
TRPV1 ProteinQ8NER1 (Uniprot-TrEMBL)
TRPV2 ProteinQ9Y5S1 (Uniprot-TrEMBL)
TRPV3 ProteinQ8NET8 (Uniprot-TrEMBL)
TRPV4 ProteinQ9HBA0 (Uniprot-TrEMBL)
TRPV5 ProteinQ9NQA5 (Uniprot-TrEMBL)
TRPV6 ProteinQ9H1D0 (Uniprot-TrEMBL)
TRPsComplexR-HSA-3295582 (Reactome)
TSC22D3 ProteinQ99576 (Uniprot-TrEMBL)
TTYH1-3ProteinQ9H313-3 (Uniprot-TrEMBL)
TTYH2 ProteinQ9BSA4 (Uniprot-TrEMBL)
TTYH2/3ComplexR-HSA-2744253 (Reactome)
TTYH3 ProteinQ9C0H2 (Uniprot-TrEMBL)
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)
UNC79 ProteinQ9P2D8 (Uniprot-TrEMBL)
UNC80 ProteinQ8N2C7 (Uniprot-TrEMBL)
Ub-SCNN channelsComplexR-HSA-2684917 (Reactome)
Ub-SCNN1A ProteinP37088 (Uniprot-TrEMBL)
Ub-SCNN1G ProteinP51170 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
V-ATPase:ATP6AP1ComplexR-HSA-5252081 (Reactome)
V-ATPaseComplexR-HSA-912600 (Reactome)
WNK1 ProteinQ9H4A3 (Uniprot-TrEMBL)
WNK2 ProteinQ9Y3S1 (Uniprot-TrEMBL)
WNK3 ProteinQ9BYP7 (Uniprot-TrEMBL)
WNK4 ProteinQ96J92 (Uniprot-TrEMBL)
WNKsComplexR-HSA-2684956 (Reactome)
WWP1 ProteinQ9H0M0 (Uniprot-TrEMBL)
amilorideMetaboliteCHEBI:2639 (ChEBI)
apoTF ProteinP02787 (Uniprot-TrEMBL)
apoTF:TFRC dimerComplexR-HSA-917833 (Reactome)
apoTF:TFRC dimerComplexR-HSA-917912 (Reactome)
apoTFProteinP02787 (Uniprot-TrEMBL)
cationMetaboliteCHEBI:36916 (ChEBI)
divalent metal cationMetaboliteCHEBI:60240 (ChEBI)
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-S-RIPK1:p-S199,227-RIPK3 oligomer R-HSA-5218908 (Reactome)
p-S-RIPK1:p-S199,227-RIPK3:p-T357,S358-MLKL oligomerComplexR-HSA-5357794 (Reactome)
p-S16-PLN ProteinP26678 (Uniprot-TrEMBL)
p-S16-PLN pentamerComplexR-HSA-5578810 (Reactome)
p-S56,S534-N-acetyl-L-alanine-FLVCR1ProteinQ9Y5Y0 (Uniprot-TrEMBL)
p-T357,S358-MLKL oligomer R-HSA-5357857 (Reactome)
urateMetaboliteCHEBI:17775 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ABCG2 dimermim-catalysisR-HSA-917979 (Reactome)
ADPArrowR-HSA-2682349 (Reactome)
ADPArrowR-HSA-5251989 (Reactome)
ADPArrowR-HSA-5692462 (Reactome)
ADPArrowR-HSA-5692480 (Reactome)
ADPArrowR-HSA-917841 (Reactome)
ADPArrowR-HSA-917979 (Reactome)
ADPArrowR-HSA-936802 (Reactome)
ADPArrowR-HSA-936883 (Reactome)
ADPArrowR-HSA-936895 (Reactome)
ADPArrowR-HSA-936897 (Reactome)
ADPArrowR-HSA-937311 (Reactome)
ADPArrowR-HSA-939763 (Reactome)
ADPArrowR-HSA-947591 (Reactome)
ANOsmim-catalysisR-HSA-2684901 (Reactome)
APLsArrowR-HSA-939763 (Reactome)
APLsArrowR-HSA-947591 (Reactome)
APLsR-HSA-939763 (Reactome)
APLsR-HSA-947591 (Reactome)
ASIC trimer:H+mim-catalysisR-HSA-2671885 (Reactome)
ASIC4TBarR-HSA-2671885 (Reactome)
ATP13A1mim-catalysisR-HSA-5692462 (Reactome)
ATP13A2mim-catalysisR-HSA-5692480 (Reactome)
ATP13A4, 5mim-catalysisR-HSA-5251989 (Reactome)
ATP1A:ATP1B:FXYDmim-catalysisR-HSA-936897 (Reactome)
ATP2A1-3mim-catalysisR-HSA-418365 (Reactome)
ATP2A1-3mim-catalysisR-HSA-427910 (Reactome)
ATP2B1-4mim-catalysisR-HSA-418309 (Reactome)
ATP2C1/2:Mg2+mim-catalysisR-HSA-936883 (Reactome)
ATP4A/12A:ATP4Bmim-catalysisR-HSA-937311 (Reactome)
ATP6AP1R-HSA-5252133 (Reactome)
ATP7A:PDZD11mim-catalysisR-HSA-936802 (Reactome)
ATP7Bmim-catalysisR-HSA-936895 (Reactome)
ATPArrowR-HSA-2855020 (Reactome)
ATPR-HSA-2682349 (Reactome)
ATPR-HSA-5251989 (Reactome)
ATPR-HSA-5692462 (Reactome)
ATPR-HSA-5692480 (Reactome)
ATPR-HSA-917841 (Reactome)
ATPR-HSA-917979 (Reactome)
ATPR-HSA-936802 (Reactome)
ATPR-HSA-936883 (Reactome)
ATPR-HSA-936895 (Reactome)
ATPR-HSA-936897 (Reactome)
ATPR-HSA-937311 (Reactome)
ATPR-HSA-939763 (Reactome)
ATPR-HSA-947591 (Reactome)
BESTsmim-catalysisR-HSA-2744361 (Reactome)
BESTsmim-catalysisR-HSA-2752067 (Reactome)
BVArrowR-HSA-189398 (Reactome)
C-terminus CLCAsArrowR-HSA-5333671 (Reactome)
CLCAsR-HSA-5333671 (Reactome)
CLCAsmim-catalysisR-HSA-5333671 (Reactome)
CLCN1/2/KA/KBmim-catalysisR-HSA-2744228 (Reactome)
CLCN3mim-catalysisR-HSA-2731002 (Reactome)
CLCN4/5/6mim-catalysisR-HSA-2730692 (Reactome)
CLCN7:OSTM1mim-catalysisR-HSA-2730959 (Reactome)
CLIC2TBarR-HSA-2855020 (Reactome)
COArrowR-HSA-189398 (Reactome)
CUTC tetramerR-HSA-5334788 (Reactome)
CUTC:4xCu+ArrowR-HSA-5334788 (Reactome)
CYBRD1:Hememim-catalysisR-HSA-917805 (Reactome)
Ca2+ArrowR-HSA-2684901 (Reactome)
Ca2+ArrowR-HSA-2685505 (Reactome)
Ca2+ArrowR-HSA-2744242 (Reactome)
Ca2+ArrowR-HSA-2744361 (Reactome)
Ca2+ArrowR-HSA-2855020 (Reactome)
Ca2+ArrowR-HSA-3295579 (Reactome)
Ca2+ArrowR-HSA-418309 (Reactome)
Ca2+ArrowR-HSA-418365 (Reactome)
Ca2+ArrowR-HSA-427910 (Reactome)
Ca2+ArrowR-HSA-5333671 (Reactome)
Ca2+ArrowR-HSA-936883 (Reactome)
Ca2+ArrowR-HSA-975311 (Reactome)
Ca2+R-HSA-2685505 (Reactome)
Ca2+R-HSA-2855020 (Reactome)
Ca2+R-HSA-3295579 (Reactome)
Ca2+R-HSA-418309 (Reactome)
Ca2+R-HSA-418365 (Reactome)
Ca2+R-HSA-427910 (Reactome)
Ca2+R-HSA-936883 (Reactome)
Ca2+R-HSA-975311 (Reactome)
Ca2+TBarR-HSA-2730664 (Reactome)
Cl-ArrowR-HSA-2684901 (Reactome)
Cl-ArrowR-HSA-2730692 (Reactome)
Cl-ArrowR-HSA-2730959 (Reactome)
Cl-ArrowR-HSA-2731002 (Reactome)
Cl-ArrowR-HSA-2744228 (Reactome)
Cl-ArrowR-HSA-2744242 (Reactome)
Cl-ArrowR-HSA-2744349 (Reactome)
Cl-ArrowR-HSA-2744361 (Reactome)
Cl-ArrowR-HSA-975340 (Reactome)
Cl-ArrowR-HSA-975389 (Reactome)
Cl-ArrowR-HSA-975449 (Reactome)
Cl-R-HSA-2684901 (Reactome)
Cl-R-HSA-2730692 (Reactome)
Cl-R-HSA-2730959 (Reactome)
Cl-R-HSA-2731002 (Reactome)
Cl-R-HSA-2744228 (Reactome)
Cl-R-HSA-2744242 (Reactome)
Cl-R-HSA-2744349 (Reactome)
Cl-R-HSA-2744361 (Reactome)
Cl-R-HSA-975340 (Reactome)
Cl-R-HSA-975389 (Reactome)
Cl-R-HSA-975449 (Reactome)
Cu1+R-HSA-5334788 (Reactome)
Cu2+ArrowR-HSA-936802 (Reactome)
Cu2+ArrowR-HSA-936895 (Reactome)
Cu2+R-HSA-936802 (Reactome)
Cu2+R-HSA-936895 (Reactome)
Fe(3+)O(OH)ArrowR-HSA-1562626 (Reactome)
Fe2+ArrowR-HSA-189398 (Reactome)
Fe2+ArrowR-HSA-435349 (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-904830 (Reactome)
Fe2+R-HSA-917891 (Reactome)
Fe2+R-HSA-917933 (Reactome)
Fe2+R-HSA-917936 (Reactome)
Fe3+ArrowR-HSA-442368 (Reactome)
Fe3+ArrowR-HSA-5671707 (Reactome)
Fe3+ArrowR-HSA-917835 (Reactome)
Fe3+ArrowR-HSA-917891 (Reactome)
Fe3+ArrowR-HSA-917933 (Reactome)
Fe3+R-HSA-442368 (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)
GABR heteropentamers:GABAmim-catalysisR-HSA-975340 (Reactome)
GABRR pentamer:GABAmim-catalysisR-HSA-975449 (Reactome)
GLRA:GLRB:Glymim-catalysisR-HSA-975389 (Reactome)
H+ArrowR-HSA-2730692 (Reactome)
H+ArrowR-HSA-2730959 (Reactome)
H+ArrowR-HSA-2731002 (Reactome)
H+ArrowR-HSA-2872444 (Reactome)
H+ArrowR-HSA-2872463 (Reactome)
H+ArrowR-HSA-2889070 (Reactome)
H+ArrowR-HSA-418365 (Reactome)
H+ArrowR-HSA-427910 (Reactome)
H+ArrowR-HSA-435349 (Reactome)
H+ArrowR-HSA-917841 (Reactome)
H+ArrowR-HSA-937311 (Reactome)
H+R-HSA-1562626 (Reactome)
H+R-HSA-2730692 (Reactome)
H+R-HSA-2730959 (Reactome)
H+R-HSA-2731002 (Reactome)
H+R-HSA-2872444 (Reactome)
H+R-HSA-2872463 (Reactome)
H+R-HSA-2889070 (Reactome)
H+R-HSA-418365 (Reactome)
H+R-HSA-427910 (Reactome)
H+R-HSA-435349 (Reactome)
H+R-HSA-917841 (Reactome)
H+R-HSA-917891 (Reactome)
H+R-HSA-917933 (Reactome)
H+R-HSA-937311 (Reactome)
H2OArrowR-HSA-189398 (Reactome)
H2OArrowR-HSA-917891 (Reactome)
H2OArrowR-HSA-917933 (Reactome)
H2OR-HSA-5251989 (Reactome)
H2OR-HSA-5692462 (Reactome)
H2OR-HSA-5692480 (Reactome)
H2OR-HSA-917841 (Reactome)
H2OR-HSA-917979 (Reactome)
H2OR-HSA-936802 (Reactome)
H2OR-HSA-936883 (Reactome)
H2OR-HSA-936895 (Reactome)
H2OR-HSA-936897 (Reactome)
H2OR-HSA-937311 (Reactome)
H2OR-HSA-939763 (Reactome)
H2OR-HSA-947591 (Reactome)
HCO3-ArrowR-HSA-2752067 (Reactome)
HCO3-R-HSA-2752067 (Reactome)
HMOX1,2mim-catalysisR-HSA-189398 (Reactome)
HTR3 pentamer:5HTmim-catalysisR-HSA-975311 (Reactome)
K+ArrowR-HSA-936897 (Reactome)
K+ArrowR-HSA-937311 (Reactome)
K+ArrowR-HSA-975311 (Reactome)
K+R-HSA-936897 (Reactome)
K+R-HSA-937311 (Reactome)
K+R-HSA-975311 (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)
MTP1:HEPH:6Cu2+mim-catalysisR-HSA-442368 (Reactome)
MTP1:HEPH:6Cu2+mim-catalysisR-HSA-917933 (Reactome)
Mn2+ArrowR-HSA-5692462 (Reactome)
Mn2+R-HSA-5692462 (Reactome)
N-terminus CLCAsArrowR-HSA-2684901 (Reactome)
N-terminus CLCAsArrowR-HSA-2744242 (Reactome)
N-terminus CLCAsArrowR-HSA-2744361 (Reactome)
N-terminus CLCAsArrowR-HSA-5333671 (Reactome)
NAADPArrowR-HSA-2685505 (Reactome)
NADP+ArrowR-HSA-189398 (Reactome)
NADPHR-HSA-189398 (Reactome)
NALCN:UNC79:UNC80mim-catalysisR-HSA-2730664 (Reactome)
NSAIDTBarR-HSA-2671885 (Reactome)
Na+/Li+ArrowR-HSA-2889070 (Reactome)
Na+/Li+R-HSA-2889070 (Reactome)
Na+ArrowR-HSA-2671885 (Reactome)
Na+ArrowR-HSA-2672334 (Reactome)
Na+ArrowR-HSA-2730664 (Reactome)
Na+ArrowR-HSA-2872444 (Reactome)
Na+ArrowR-HSA-2872463 (Reactome)
Na+ArrowR-HSA-2872498 (Reactome)
Na+ArrowR-HSA-3295580 (Reactome)
Na+ArrowR-HSA-936897 (Reactome)
Na+ArrowR-HSA-975311 (Reactome)
Na+R-HSA-2671885 (Reactome)
Na+R-HSA-2672334 (Reactome)
Na+R-HSA-2730664 (Reactome)
Na+R-HSA-2872444 (Reactome)
Na+R-HSA-2872463 (Reactome)
Na+R-HSA-2872498 (Reactome)
Na+R-HSA-3295580 (Reactome)
Na+R-HSA-936897 (Reactome)
Na+R-HSA-975311 (Reactome)
O2R-HSA-1562626 (Reactome)
O2R-HSA-189398 (Reactome)
O2R-HSA-917891 (Reactome)
O2R-HSA-917933 (Reactome)
P-type ATPases type IVmim-catalysisR-HSA-939763 (Reactome)
P-type ATPases type IVmim-catalysisR-HSA-947591 (Reactome)
PLN pentamerTBarR-HSA-427910 (Reactome)
PiArrowR-HSA-2682349 (Reactome)
PiArrowR-HSA-2872498 (Reactome)
PiArrowR-HSA-5251989 (Reactome)
PiArrowR-HSA-5692462 (Reactome)
PiArrowR-HSA-5692480 (Reactome)
PiArrowR-HSA-917841 (Reactome)
PiArrowR-HSA-917979 (Reactome)
PiArrowR-HSA-936802 (Reactome)
PiArrowR-HSA-936883 (Reactome)
PiArrowR-HSA-936895 (Reactome)
PiArrowR-HSA-936897 (Reactome)
PiArrowR-HSA-937311 (Reactome)
PiArrowR-HSA-939763 (Reactome)
PiArrowR-HSA-947591 (Reactome)
PiR-HSA-2872498 (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-2671885 (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).
R-HSA-2672334 (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).
R-HSA-2682349 (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).
R-HSA-2684901 (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).
R-HSA-2685505 (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).
R-HSA-2730664 (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).
R-HSA-2730692 (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.
R-HSA-2730959 (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).
R-HSA-2731002 (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).
R-HSA-2744228 (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).
R-HSA-2744242 (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).
R-HSA-2744349 (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).
R-HSA-2744361 (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).
R-HSA-2752067 (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).
R-HSA-2855020 (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, Lanner et al. 2010). The function of RYRs are controlled by peptidyl-prolyl cis-trans isomerase (FKBP1B), 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 polymerise (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 (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). Protein kinase A (PKA) phosphorylation of RYR2 dissociates FKBP1B and results in defective channel function (Marx et al. 2000). The penta-EF hand protein sorcin (SRI) can modulate Ca2+-induced calcium-release in the heart via the interaction with several Ca2+ channels such as RYRs. A natural ligand, F112L, impairs this modulating activity (Franceschini et al. 2008).
R-HSA-2872444 (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.
R-HSA-2872463 (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).
R-HSA-2872497 (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.
R-HSA-2872498 (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).
R-HSA-2889070 (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.
R-HSA-3295579 (Reactome) All functionally characterized TRP channels are permeable to the divalent cation Ca2+ except TRPM4 and 5 (Latorre et al. 2009, Wu et al. 2010).
R-HSA-3295580 (Reactome) Most members of the TRP channel family are permeable to Ca2+. Although TRPM4 and 5 can be activated by increased levels of intracellular Ca2+, they are impermeable to it. Instead, they are monovalent-selective with highest affinity for Na+ transport, of which leads to depolarization of the membrane (Launay et al. 2002, Prawitt et al. 2003). They play a central role in cardiomyocytes, neurons, endocrine pancreas cells, kidney epithelial cells and cochlea hair cells.
R-HSA-418309 (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.
R-HSA-418365 (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.
R-HSA-427910 (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.
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-5251989 (Reactome) Probable cation-transporting ATPases 13A4 and 13A5 (ATP13A4, 5) belong to the P5 subfamily of P-tpre ATPases. This subfamily is the most poorly understood in terms of chracterisation and function. The yeast orthologue YPK9 (aka Yor291w) shows toxicity when deleted from yeast cells, suggesting a role in sequestration of divalent heavy metal ions (Schmidt et al. 2009). The ATP13A4 gene may be disrupted by a 3q25-q29 inversion of the long arm of chromosome 3, which may result in a specific language impairment (SLI) (Kwasnicka-Crawford et al. 2005).
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-5333671 (Reactome) Calcium-activated chloride channel regulators 1,2,3P and 4 (CLCA1,2,3P and 4), originally named as CLCAs based on the observation that overexpression of them all induced chloride current in response to cytosolic calcium flux. More recent evidence points to them being secreted proteins (Gibson et al. 2005) and being responsible for chloride channel modulation rather that forming chloride channels per se (Hamann et al. 2009). CLCA1 has been found to be overexpressed in aiways of patients suffering from asthma and chronic obstructive pulmonary disease (Hoshino et al. 2002, Toda et al. 2002, Kamada et al. 2004). All CLCAs contain a consensus cleavage motif which is recognised by an internal zincin metalloprotease domain within the N terminus. Self-proteolysis within the secretory pathway yields N- and C-terminal fragments, a step critical for CLCA activation of calcium-activated chloride channels (CaCCs) mediated through the N-terminal fragment (Yurtsever et al. 2012).
R-HSA-5334788 (Reactome) A potential regulator of human copper metabolism has recently been described. Copper homeostasis protein cutC homolog (CutC) is a highly conserved cytosolic copper binding protein (Li et al. 2005, Li et al. 2010). Its function in human copper metabolism remains unclear but in C. elegans, the orthologous cutc1 protein down-regulation increases sensitivity to high levels of copper (Calafato et al. 2008).
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-5692462 (Reactome) Manganese-transporting ATPase 13A1 (ATP13A1) mediates the transport of manganese (Mn2+) into the endoplasmic reticulum. ATPase activity is required for cellular manganese homeostasis (Cohen et al. 2013).
R-HSA-5692480 (Reactome) The probable cation-transporting ATPase 13A2 (ATP13A2) is thought to play a role in intracellular cation homeostasis and the maintenance of neuronal integrity (Ramonet et al. 2012). Defects in ATP13A2 can cause Kufor-Rakeb syndrome (KRS; MIM:606693), a juvenile-onset Levodopa-responsive parkinsonism (Lai et al. 2012).
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).
R-HSA-936802 (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).
R-HSA-936883 (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).
R-HSA-936895 (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).
R-HSA-936897 (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).
R-HSA-937311 (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).
R-HSA-939763 (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).
R-HSA-947591 (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).
R-HSA-975311 (Reactome) The 5-hydroxytryptamine receptor (HTR3) family are members of the superfamily of ligand-gated ion channels (LGICs). Five receptors (HTR3A-E) can form a homopentamer (HTR3A) or heteropentamers (HTR3A with B, C, D or E) (Barrera et al. 2005, Niesler et al. 2007; reviews - Barnes et al. 2009, Wu et al. 2015) Although heterpentamer composition can vary between the two receptors binding, the example 2xHTR3A:3xHTR3(B-E) is shown here. 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).
R-HSA-975340 (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), 2 gamma subunits (GABRG) (Khan et al. 1993, Hadingham et al. 1995) and a theta subunit (Bonnert et al. 1999) characterised to date. GABA(A) functions as a heteropentamer, the most common structure being 2 alpha subunits, 2 beta subunits and a gamma subunit (2GABRA:2GABRB:GABRG). An alternative heteropentamer with much less affinity for GABA is 2GABRA:GABRB:GABRG:GABRQ (Bonnert et al. 1999). Upon binding of GABA, both GABR complexes conduct chloride ions through their pore, resulting in hyperpolarisation of the neuron. This causes an inhibitory effect on neurotransmission by reducing the chances of a successful action potential occurring.
R-HSA-975389 (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).
R-HSA-975449 (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).
RAF1:SGK:TSC22D3:WPPmim-catalysisR-HSA-2682349 (Reactome)
RYR

tetramer:FKBP1B tetramer:CASQ

polymer:TRDN:junctin		mim-catalysisR-HSA-2855020 (Reactome)
SCNN channelsR-HSA-2682349 (Reactome)
SCNN channelsmim-catalysisR-HSA-2672334 (Reactome)
SLC11A2mim-catalysisR-HSA-435349 (Reactome)
SLC17A3(1-498)mim-catalysisR-HSA-2872497 (Reactome)
SLC17A3mim-catalysisR-HSA-2872498 (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)
SLC46A1mim-catalysisR-HSA-917870 (Reactome)
SLC9B1/C2mim-catalysisR-HSA-2872444 (Reactome)
SLC9B2mim-catalysisR-HSA-2889070 (Reactome)
SLC9C1mim-catalysisR-HSA-2872463 (Reactome)
SRIArrowR-HSA-2855020 (Reactome)
STEAP3-like proteinsmim-catalysisR-HSA-917811 (Reactome)
TFRC dimerArrowR-HSA-917839 (Reactome)
TFRC dimerR-HSA-917987 (Reactome)
TPCN1/2mim-catalysisR-HSA-2685505 (Reactome)
TRPM4,5mim-catalysisR-HSA-3295580 (Reactome)
TRPsmim-catalysisR-HSA-3295579 (Reactome)
TTYH1-3mim-catalysisR-HSA-2744349 (Reactome)
TTYH2/3mim-catalysisR-HSA-2744242 (Reactome)
Ub-SCNN channelsArrowR-HSA-2682349 (Reactome)
UbR-HSA-2682349 (Reactome)
V-ATPase:ATP6AP1ArrowR-HSA-5252133 (Reactome)
V-ATPase:ATP6AP1mim-catalysisR-HSA-917841 (Reactome)
V-ATPaseR-HSA-5252133 (Reactome)
WNKsArrowR-HSA-2682349 (Reactome)
amilorideTBarR-HSA-2671885 (Reactome)
amilorideTBarR-HSA-2672334 (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)
cationArrowR-HSA-5692480 (Reactome)
cationR-HSA-5692480 (Reactome)
divalent metal cationArrowR-HSA-5251989 (Reactome)
divalent metal cationR-HSA-5251989 (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-917987 (Reactome)
p-S-RIPK1:p-S199,227-RIPK3:p-T357,S358-MLKL oligomerArrowR-HSA-3295579 (Reactome)
p-S16-PLN pentamerArrowR-HSA-427910 (Reactome)
p-S56,S534-N-acetyl-L-alanine-FLVCR1mim-catalysisR-HSA-917892 (Reactome)
urateArrowR-HSA-2872497 (Reactome)
urateR-HSA-2872497 (Reactome)
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