Erythrocytes take up oxygen and release carbon dioxide (Homo sapiens)

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3, 4, 178, 9, 20, 22, 26...25, 27, 3119, 34, 3915, 27, 31, 37, 381, 7, 12, 14, 21...2, 6, 10, 13, 28...cytosolZn2+ O2 Cl-SLC4A1 dimerH+Cl-RHAGCA4:Zn2+H+heme AQP1 tetramerZn2+ H2OCA1,2HCO3-HBB CO2CA2 H2OSLC4A1 HCO3-CO2heme N-seryl-glycosylphosphatidylinositolethanolamine-CA4 AQP1 OxyHbAProtonated CarbaminoDeoxyHbACO-H+-HBA1 HBA1 O2CO-H+-HBB CA1 18, 24, 325, 11, 4116


Erythrocytes circulating through the capillaries of the lung must exchange carbon dioxide (CO2) for oxygen (O2) during their short (0.5-1 sec.) transit time in pulmonary tissue (Reviewed in Jensen 2004, Esbaugh and Tufts 2006, Boron 2010). CO2 bound as carbamate to the N-terminus of hemoglobin and protons (H+) bound to histidine residues in hemoglobin are released as hemoglobin (HbA) binds O2. Bicarbonate (HCO3-) present in plasma is taken up by erythrocytes via the band3 anion exchanger (AE1, SLC4A1) and combined with H+ by carbonic anhydrases I and II (CA1/CA2) to yield water and CO2 (Reviewed by Esbaugh and Tufts 2006). CO2 is passively transported out of the erythrocyte by AQP1 and RhAG. HCO3- in plasma is also directly dehydrated by extracellular carbonic anhydrase IV (CA4) present on endothelial cells lining the capillaries in the lung. View original pathway at Reactome.


Pathway is converted from Reactome ID: 1247673
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  20. Innocenti A, Firnges MA, Antel J, Wurl M, Scozzafava A, Supuran CT.; ''Carbonic anhydrase inhibitors: inhibition of the membrane-bound human isozyme IV with anions.''; PubMed Europe PMC Scholia
  21. Tazawa H, Mochizuki M, Tamura M, Kagawa T.; ''Quantitative analyses of the CO2 dissociation curve of oxygenated blood and the Haldane effect in human blood.''; PubMed Europe PMC Scholia
  22. Baird TT, Waheed A, Okuyama T, Sly WS, Fierke CA.; ''Catalysis and inhibition of human carbonic anhydrase IV.''; PubMed Europe PMC Scholia
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  43. Kernohan JC, Roughton FJ.; ''Thermal studies of the rates of the reactions of carbon dioxide in concentrated haemoglobin solutions and in red blood cells. A. The reactions catalysed by carbonic anhydrase. B. The carbamino reactions of oxygenated and deoxygenated haemoglobin.''; PubMed Europe PMC Scholia


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114973view16:50, 25 January 2021ReactomeTeamReactome version 75
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112619view15:59, 9 October 2020ReactomeTeamReactome version 73
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93402view11:22, 9 August 2017ReactomeTeamreactome version 61
87442view13:40, 22 July 2016MkutmonOntology Term : 'classic metabolic pathway' added !
86488view09:19, 11 July 2016ReactomeTeamreactome version 56
83368view11:01, 18 November 2015ReactomeTeamVersion54
81750view09:50, 26 August 2015ReactomeTeamVersion53
76878view08:15, 17 July 2014ReactomeTeamFixed remaining interactions
76583view11:56, 16 July 2014ReactomeTeamFixed remaining interactions
75916view09:57, 11 June 2014ReactomeTeamRe-fixing comment source
75616view10:48, 10 June 2014ReactomeTeamReactome 48 Update
74971view13:49, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74615view08:40, 30 April 2014ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
AQP1 ProteinP29972 (Uniprot-TrEMBL)
AQP1 tetramerComplexR-HSA-432246 (Reactome)
CA1 ProteinP00915 (Uniprot-TrEMBL)
CA1,2ComplexR-HSA-1475437 (Reactome)
CA2 ProteinP00918 (Uniprot-TrEMBL)
CA4:Zn2+ComplexR-HSA-1237308 (Reactome)
CO-H+-HBA1 ProteinP69905 (Uniprot-TrEMBL)
CO-H+-HBB ProteinP68871 (Uniprot-TrEMBL)
CO2MetaboliteCHEBI:16526 (ChEBI)
Cl-MetaboliteCHEBI:17996 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HBA1 ProteinP69905 (Uniprot-TrEMBL)
HBB ProteinP68871 (Uniprot-TrEMBL)
HCO3-MetaboliteCHEBI:17544 (ChEBI)
N-seryl-glycosylphosphatidylinositolethanolamine-CA4 ProteinP22748 (Uniprot-TrEMBL)
O2 MetaboliteCHEBI:15379 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
OxyHbAComplexR-HSA-1237320 (Reactome)
Protonated Carbamino DeoxyHbAComplexR-HSA-1237312 (Reactome)
RHAGProteinQ02094 (Uniprot-TrEMBL)
SLC4A1 ProteinP02730 (Uniprot-TrEMBL)
SLC4A1 dimerComplexR-HSA-1244330 (Reactome)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
heme MetaboliteCHEBI:17627 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AQP1 tetramermim-catalysisR-HSA-1247649 (Reactome)
CA1,2mim-catalysisR-HSA-1475436 (Reactome)
CA4:Zn2+mim-catalysisR-HSA-1237059 (Reactome)
CO2ArrowR-HSA-1237059 (Reactome)
CO2ArrowR-HSA-1247645 (Reactome)
CO2ArrowR-HSA-1247649 (Reactome)
CO2ArrowR-HSA-1247668 (Reactome)
CO2ArrowR-HSA-1475436 (Reactome)
CO2R-HSA-1247645 (Reactome)
CO2R-HSA-1247649 (Reactome)
Cl-ArrowR-HSA-1247665 (Reactome)
Cl-R-HSA-1247665 (Reactome)
H+ArrowR-HSA-1247668 (Reactome)
H+R-HSA-1237059 (Reactome)
H+R-HSA-1475436 (Reactome)
H2OArrowR-HSA-1237059 (Reactome)
H2OArrowR-HSA-1475436 (Reactome)
HCO3-ArrowR-HSA-1247665 (Reactome)
HCO3-R-HSA-1237059 (Reactome)
HCO3-R-HSA-1247665 (Reactome)
HCO3-R-HSA-1475436 (Reactome)
O2R-HSA-1247668 (Reactome)
OxyHbAArrowR-HSA-1247668 (Reactome)
Protonated Carbamino DeoxyHbAR-HSA-1247668 (Reactome)
R-HSA-1237059 (Reactome) Carbonic anhydrase IV (CA4) located on the extracellular face of the plasma membrane (Wistrand et al. 1999) dehydrates bicarbonate (HCO3--) to yield water and carbon dioxide (CO2) (Zhu & Sly 1990, Okayuma et al. 1992, Baird et al. 1997, Innocenti et al. 2004, reviewed in Lindskog 1997). Depending on the concentrations of reactants the reaction is reversible.
R-HSA-1247645 (Reactome) The Rhesus blood group type A glycoprotein (RhAG) passively transports carbon dioxide (CO2) across the plasma membrane according to the concentration gradient (Endeward et al. 2006, Endeward et al. 2008, Musa-Aziz et al. 2009).
R-HSA-1247649 (Reactome) Aquaporin-1 (AQP1) passively transports carbon dioxide (CO2) across the plasma membrane according to the concentration gradient (Nakhoul et al. 1998, Blank & Ehmke et al. 2003, Endeward et al. 2006, Musa-Aziz et al. 2009). The pore in AQP1 that conducts CO2 may be distinct from the pore that conducts water.
R-HSA-1247665 (Reactome) The band 3 anion exchange protein (AE1, SLC4A1) exchanges chloride (Cl-) for bicarbonate (HCO3-) across the plasma membrane according to the concentration gradients of the anions (Knauf et al. 1996, Dahl et al. 2003). SLC4A1 may be part of a complex ("metabolon") with carbonic anhydrase II (CA2) which would facilitate the transport of HCO3- (Sterling et al. 2001).
R-HSA-1247668 (Reactome) The binding of oxygen (O2) to hemoglobin (HbA) decreases the affinity of HbA for protons (H+) bound at histidine residues and carbon dioxide (CO2) bound chemically as a carbamate at the N-terminus of the HbA (Ferguson and Roughton 1934, Kernohan & Roughton 1968, Klocke 1973, Morrow et al. 1973, Morrow et al. 1976, Tazawa et al. 1983, Kraan & Rispens 1985, Doyle et al. 1987, Mertzlufft & Brandt 1989, Kalhoff et al.1994, Dash & Bassingthwaighte 2010, reviewed in Jensen 2004). This property of HbA is known as the Haldane Effect and facilitates the exchange of CO2 for O2 in the lungs.
R-HSA-1475436 (Reactome) Carbonic anhydrase I (CA1, Khalifah 1971, Pesando 1975, Simonsson et al. 1982, Ren & Lindskog 1992) and carbonic anhydrase II (CA2, Tibell et al. 1984, Jones & Shaw 1983, Ghannam et al. 1986) hydrate carbon dioxide (CO2) to yield bicarbonate (HCO3-) and a proton (H+). During the reaction a hydroxyl group bound by the zinc ion (Zn2+) attacks the CO2 molecule in the active site to directly form HCO3- (reviewed in Lindskog 1997). The HCO3- is displaced by water, which is then deprotonated by a histidine residue to recreate the Zn2+:hydroxyl group. Depending on the concentrations of reactants the reaction is reversible.
RHAGmim-catalysisR-HSA-1247645 (Reactome)
SLC4A1 dimermim-catalysisR-HSA-1247665 (Reactome)
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