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

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14, 26, 317, 13, 242, 8, 12, 15-18, 32...21, 22, 28, 34, 40...1, 10, 205, 30, 33, 38, 40...3, 4, 291, 6, 10, 19, 23cytosolH+HBB CA1 AQP1 N-seryl-glycosylphosphatidylinositolethanolamine-CA4 HCO3-H2OHBA1 HBB CYB5R1 CA2 CYB5RL heme H+CYB5RsCO-H+-HBB HBB CO-H+-HBA1 CYB5R4 RHAGheme Protonated CarbaminoDeoxyHbACA4:Zn2+AQP1 tetramerCO2HBA1 O2FeHM O2 Cl-Zn2+ MetHbOxyHbAHbACO2CA1,2NADHZn2+ Cl-SLC4A1 dimerH+SLC4A1 H2ONAD+HBA1 heme CYB5R2 HCO3-479, 27, 3711, 25, 42


Carbon dioxide (CO2) in plasma is hydrated to yield protons (H+) and bicarbonate (HCO3-) by carbonic anhydrase IV (CA4) located on the apical plasma membranes of endothelial cells. Plasma CO2 is also taken up by erythrocytes via AQP1 and RhAG. Within erythrocytes CA1 and, predominantly, CA2 hydrate CO2 to HCO3- and protons (reviewed in Geers & Gros 2000, Jensen 2004, Boron 2010). The HCO3- is transferred out of the erythrocyte by the band 3 anion exchange protein (AE1, SLC4A1) which cotransports a chloride ion (Cl-) into the erythrocyte.
Also within the erythrocyte, CO2 combines with the N-terminal alpha amino groups of HbA to form carbamates while protons bind histidine residues in HbA. The net result is the Bohr effect, a conformational change in HbA that reduces its affinity for O2 and hence assists the delivery of O2 to tissues. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 1237044
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce

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  1. Musa-Aziz R, Chen LM, Pelletier MF, Boron WF.; ''Relative CO2/NH3 selectivities of AQP1, AQP4, AQP5, AmtB, and RhAG.''; PubMed Europe PMC
  2. Fang TY, Zou M, Simplaceanu V, Ho NT, Ho C.; ''Assessment of roles of surface histidyl residues in the molecular basis of the Bohr effect and of beta 143 histidine in the binding of 2,3-bisphosphoglycerate in human normal adult hemoglobin.''; PubMed Europe PMC
  3. Zhu H, Qiu H, Yoon HW, Huang S, Bunn HF.; ''Identification of a cytochrome b-type NAD(P)H oxidoreductase ubiquitously expressed in human cells.''; PubMed Europe PMC
  4. Baker MA, Krutskikh A, Curry BJ, Hetherington L, Aitken RJ.; ''Identification of cytochrome-b5 reductase as the enzyme responsible for NADH-dependent lucigenin chemiluminescence in human spermatozoa.''; PubMed Europe PMC
  5. Baird TT, Waheed A, Okuyama T, Sly WS, Fierke CA.; ''Catalysis and inhibition of human carbonic anhydrase IV.''; PubMed Europe PMC
  6. Endeward V, Musa-Aziz R, Cooper GJ, Chen LM, Pelletier MF, Virkki LV, Supuran CT, King LS, Boron WF, Gros G.; ''Evidence that aquaporin 1 is a major pathway for CO2 transport across the human erythrocyte membrane.''; PubMed Europe PMC
  7. Knauf PA, Gasbjerg PK, Brahm J.; ''The asymmetry of chloride transport at 38 degrees C in human red blood cell membranes.''; PubMed Europe PMC
  8. 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
  9. de Groot BL, Engel A, Grubmüller H.; ''A refined structure of human aquaporin-1.''; PubMed Europe PMC
  10. Endeward V, Cartron JP, Ripoche P, Gros G.; ''Red cell membrane CO2 permeability in normal human blood and in blood deficient in various blood groups, and effect of DIDS.''; PubMed Europe PMC
  11. Pinder JC, Pekrun A, Maggs AM, Brain AP, Gratzer WB.; ''Association state of human red blood cell band 3 and its interaction with ankyrin.''; PubMed Europe PMC
  12. Kwant G, Oeseburg B, Zwart A, Zijlstra WG.; ''Human whole-blood O2 affinity: effect of CO2.''; PubMed Europe PMC
  13. Sterling D, Reithmeier RA, Casey JR.; ''A transport metabolon. Functional interaction of carbonic anhydrase II and chloride/bicarbonate exchangers.''; PubMed Europe PMC
  14. Boron WF.; ''Evaluating the role of carbonic anhydrases in the transport of HCO3--related species.''; PubMed Europe PMC
  15. Bauer C, Schröder E.; ''Carbamino compounds of haemoglobin in human adult and foetal blood.''; PubMed Europe PMC
  16. Matthew JB, Morrow JS, Wittebort RJ, Gurd FR.; ''Quantitative determination of carbamino adducts of alpha and beta chains in human adult hemoglobin in presence and absence of carbon monoxide and 2,3-diphosphoglycerate.''; PubMed Europe PMC
  17. Morrow JS, Matthew JB, Wittebort RJ, Gurd FR.; ''Carbon 13 resonances of 13CO2 carbamino adducts of alpha and beta chains in human adult hemoglobin.''; PubMed Europe PMC
  18. Ferguson JK, Roughton FJ.; ''The chemical relationships and physiological importance of carbamino compounds of CO(2) with haemoglobin.''; PubMed Europe PMC
  19. Nakhoul NL, Davis BA, Romero MF, Boron WF.; ''Effect of expressing the water channel aquaporin-1 on the CO2 permeability of Xenopus oocytes.''; PubMed Europe PMC
  20. Endeward V, Cartron JP, Ripoche P, Gros G.; ''RhAG protein of the Rhesus complex is a CO2 channel in the human red cell membrane.''; PubMed Europe PMC
  21. Khalifah RG.; ''The carbon dioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic studies on the native human isoenzymes B and C.''; PubMed Europe PMC
  22. Pesando JM.; ''Proton magnetic resonance studies of carbonic anhydrase. II. Group controlling catalytic activity.''; PubMed Europe PMC
  23. Blank ME, Ehmke H.; ''Aquaporin-1 and HCO3(-)-Cl- transporter-mediated transport of CO2 across the human erythrocyte membrane.''; PubMed Europe PMC
  24. Dahl NK, Jiang L, Chernova MN, Stuart-Tilley AK, Shmukler BE, Alper SL.; ''Deficient HCO3- transport in an AE1 mutant with normal Cl- transport can be rescued by carbonic anhydrase II presented on an adjacent AE1 protomer.''; PubMed Europe PMC
  25. Taylor AM, Boulter J, Harding SE, Cölfen H, Watts A.; ''Hydrodynamic properties of human erythrocyte band 3 solubilized in reduced Triton X-100.''; PubMed Europe PMC
  26. Geers C, Gros G.; ''Carbon dioxide transport and carbonic anhydrase in blood and muscle.''; PubMed Europe PMC
  27. Walz T, Hirai T, Murata K, Heymann JB, Mitsuoka K, Fujiyoshi Y, Smith BL, Agre P, Engel A.; ''The three-dimensional structure of aquaporin-1.''; PubMed Europe PMC
  28. Ghannam AF, Tsen W, Rowlett RS.; ''Activation parameters for the carbonic anhydrase II-catalyzed hydration of CO2.''; PubMed Europe PMC
  29. Zhu H, Larade K, Jackson TA, Xie J, Ladoux A, Acker H, Berchner-Pfannschmidt U, Fandrey J, Cross AR, Lukat-Rodgers GS, Rodgers KR, Bunn HF.; ''NCB5OR is a novel soluble NAD(P)H reductase localized in the endoplasmic reticulum.''; PubMed Europe PMC
  30. Okuyama T, Sato S, Zhu XL, Waheed A, Sly WS.; ''Human carbonic anhydrase IV: cDNA cloning, sequence comparison, and expression in COS cell membranes.''; PubMed Europe PMC
  31. Jensen FB.; ''Red blood cell pH, the Bohr effect, and other oxygenation-linked phenomena in blood O2 and CO2 transport.''; PubMed Europe PMC
  32. Morrow JS, Keim P, Visscher RB, Marshall RC, Gurd FR.; ''Interaction of 13 CO 2 and bicarbonate with human hemoglobin preparations.''; PubMed Europe PMC
  33. 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
  34. Simonsson I, Jonsson BH, Lindskog S.; ''A 13C nuclear magnetic resonance study of CO2/HCO-3 exchange catalyzed by human carbonic anhydrase I.''; PubMed Europe PMC
  35. Acharya AS, Bobelis DJ, White SP.; ''Electrostatic modification at the amino termini of hemoglobin A.''; PubMed Europe PMC
  36. Kovalevsky AY, Chatake T, Shibayama N, Park SY, Ishikawa T, Mustyakimov M, Fisher Z, Langan P, Morimoto Y.; ''Direct determination of protonation states of histidine residues in a 2 A neutron structure of deoxy-human normal adult hemoglobin and implications for the Bohr effect.''; PubMed Europe PMC
  37. Murata K, Mitsuoka K, Hirai T, Walz T, Agre P, Heymann JB, Engel A, Fujiyoshi Y.; ''Structural determinants of water permeation through aquaporin-1.''; PubMed Europe PMC
  38. Zhu XL, Sly WS.; ''Carbonic anhydrase IV from human lung. Purification, characterization, and comparison with membrane carbonic anhydrase from human kidney.''; PubMed Europe PMC
  39. Dash RK, Bassingthwaighte JB.; ''Erratum to: Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels.''; PubMed Europe PMC
  40. Lindskog S.; ''Structure and mechanism of carbonic anhydrase.''; PubMed Europe PMC
  41. Jones GL, Shaw DC.; ''A chemical and enzymological comparison of the common major human erythrocyte carbonic anhydrase II, its minor component, and a new genetic variant, CA II Melbourne (237 Pro leads to His).''; PubMed Europe PMC
  42. Salhany JM, Cordes KA, Sloan RL.; ''Gel filtration chromatographic studies of the isolated membrane domain of band 3.''; PubMed Europe PMC
  43. Forster RE, Constantine HP, Craw MR, Rotman HH, Klocke RA.; ''Reaction of CO2 with human hemoglobin solution.''; PubMed Europe PMC
  44. Tibell L, Forsman C, Simonsson I, Lindskog S.; ''Anion inhibition of CO2 hydration catalyzed by human carbonic anhydrase II. Mechanistic implications.''; PubMed Europe PMC
  45. Kovalevsky A, Chatake T, Shibayama N, Park SY, Ishikawa T, Mustyakimov M, Fisher SZ, Langan P, Morimoto Y.; ''Protonation states of histidine and other key residues in deoxy normal human adult hemoglobin by neutron protein crystallography.''; PubMed Europe PMC
  46. Chatake T, Shibayama N, Park SY, Kurihara K, Tamada T, Tanaka I, Niimura N, Kuroki R, Morimoto Y.; ''Protonation states of buried histidine residues in human deoxyhemoglobin revealed by neutron crystallography.''; PubMed Europe PMC
  47. Okuyama T, Waheed A, Kusumoto W, Zhu XL, Sly WS.; ''Carbonic anhydrase IV: role of removal of C-terminal domain in glycosylphosphatidylinositol anchoring and realization of enzyme activity.''; PubMed Europe PMC
  48. Wistrand PJ, Carter ND, Conroy CW, Mahieu I.; ''Carbonic anhydrase IV activity is localized on the exterior surface of human erythrocytes.''; PubMed Europe PMC
  49. Rossi-Bernardi L, Roughton FJ.; ''The specific influence of carbon dioxide and carbamate compounds on the buffer power and Bohr effects in human haemoglobin solutions.''; PubMed Europe PMC
  50. Ren X, Lindskog S.; ''Buffer dependence of CO2 hydration catalyzed by human carbonic anhydrase I.''; PubMed Europe PMC


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101201view11:10, 1 November 2018ReactomeTeamreactome version 66
100739view20:34, 31 October 2018ReactomeTeamreactome version 65
100283view19:11, 31 October 2018ReactomeTeamreactome version 64
99829view15:55, 31 October 2018ReactomeTeamreactome version 63
99386view14:33, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99084view12:39, 31 October 2018ReactomeTeamreactome version 62
93916view13:44, 16 August 2017ReactomeTeamreactome version 61
93492view11:25, 9 August 2017ReactomeTeamreactome version 61
87441view13:40, 22 July 2016MkutmonOntology Term : 'classic metabolic pathway' added !
86588view09:21, 11 July 2016ReactomeTeamreactome version 56
83189view10:19, 18 November 2015ReactomeTeamVersion54
81766view10:11, 26 August 2015ReactomeTeamVersion53
76982view08:27, 17 July 2014ReactomeTeamFixed remaining interactions
76687view12:05, 16 July 2014ReactomeTeamFixed remaining interactions
76014view10:07, 11 June 2014ReactomeTeamRe-fixing comment source
75722view11:18, 10 June 2014ReactomeTeamReactome 48 Update
75073view14:02, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74719view08:47, 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)
CYB5R1 ProteinQ9UHQ9 (Uniprot-TrEMBL)
CYB5R2 ProteinQ6BCY4 (Uniprot-TrEMBL)
CYB5R4 ProteinQ7L1T6 (Uniprot-TrEMBL)
CYB5RL ProteinQ6IPT4 (Uniprot-TrEMBL)
CYB5RsComplexR-HSA-6806851 (Reactome)
Cl-MetaboliteCHEBI:17996 (ChEBI)
FeHM MetaboliteCHEBI:36144 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HBA1 ProteinP69905 (Uniprot-TrEMBL)
HBB ProteinP68871 (Uniprot-TrEMBL)
HCO3-MetaboliteCHEBI:17544 (ChEBI)
HbAComplexR-HSA-9033252 (Reactome)
MetHbComplexR-HSA-9033251 (Reactome)
N-seryl-glycosylphosphatidylinositolethanolamine-CA4 ProteinP22748 (Uniprot-TrEMBL)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
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-1237042 (Reactome)
CA1,2mim-catalysisR-HSA-1475435 (Reactome)
CA4:Zn2+mim-catalysisR-HSA-1237047 (Reactome)
CO2ArrowR-HSA-1237042 (Reactome)
CO2ArrowR-HSA-1237069 (Reactome)
CO2R-HSA-1237042 (Reactome)
CO2R-HSA-1237047 (Reactome)
CO2R-HSA-1237069 (Reactome)
CO2R-HSA-1237325 (Reactome)
CO2R-HSA-1475435 (Reactome)
CYB5Rsmim-catalysisR-HSA-6806831 (Reactome)
Cl-ArrowR-HSA-1237038 (Reactome)
Cl-R-HSA-1237038 (Reactome)
H+ArrowR-HSA-1237047 (Reactome)
H+ArrowR-HSA-1475435 (Reactome)
H+ArrowR-HSA-6806831 (Reactome)
H+R-HSA-1237325 (Reactome)
H2OR-HSA-1237047 (Reactome)
H2OR-HSA-1475435 (Reactome)
HCO3-ArrowR-HSA-1237038 (Reactome)
HCO3-ArrowR-HSA-1237047 (Reactome)
HCO3-ArrowR-HSA-1475435 (Reactome)
HCO3-R-HSA-1237038 (Reactome)
HbAArrowR-HSA-6806831 (Reactome)
MetHbR-HSA-6806831 (Reactome)
NAD+ArrowR-HSA-6806831 (Reactome)
NADHR-HSA-6806831 (Reactome)
O2ArrowR-HSA-1237325 (Reactome)
OxyHbAR-HSA-1237325 (Reactome)
Protonated Carbamino DeoxyHbAArrowR-HSA-1237325 (Reactome)
R-HSA-1237038 (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-1237042 (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-1237047 (Reactome) Carbonic anhydrase IV (CA4) anchored to extracellular face of the plasma membrane (Wistrand et al. 1999) hydrates carbon dioxide (CO2) to yield bicarbonate (HCO3-) and a proton (H+) (Zhu & Sly 1990, Okayuma et al. 1992, Baird et al. 1997, Innocenti et al. 2004). During the reaction a hydroxyl group bound by the zinc ion (Zn2+) of CA4 attacks the CO2 molecule 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.
R-HSA-1237069 (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-1237325 (Reactome) The Bohr effect refers to the observation that carbon dioxide (CO2) decreases the affinity of hemoglobin (HbA) for oxygen (O2) (Rossi-Bernardi & Roughton 1967, Kwant et al. 1988, Dash & Bassingthwaighte 2010). The Bohr effect has two components: protonation of histidines in HbA (Chatake et al. 2007, Kovalevsky et al. 2010, Fang et al. 1999) and chemical reaction (carbamation) of the N-terminal valines of HbA by CO2 (Ferguson & Roughton 1934, Forster et al. 1968, Bauer & Schroder 1972, Morrow et al. 1973, Morrow et al. 1976, Mathew et al. 1977, Acharya et al. 1994). The protons (H+) for this reaction are produced by carbonic anhydrase acting on water and CO2 to produce bicarbonate (HCO3-) and H+ (Kernohan & Roughton 1968).
R-HSA-1475435 (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.
R-HSA-6806831 (Reactome) NADH-Cytochrome b5 reductases (CYB5Rs), flavoproteins consisting of NADH and flavin adenine dinucleotide (FAD) binding domains, catalyse electron transfer from the two-electron carrier NADH to the one-electron carrier ferricytochrome b5 ((Fe(3+)Cb5), forming ferrocytochrome b5 ((Fe(2+)Cb5) (Zhu et al. 1999, Baker et al. 2005, Zhu et al. 2004). CYB5Rs participate in fatty acid synthesis, cholesterol synthesis and xenobiotic oxidation as members of the electron transport chain on the endoplasmic reticulum membrane. In erythrocytes, CYB5Rs participate in the reduction of methemoglobin (MetHb) to hemoglobin A (HbA).
RHAGmim-catalysisR-HSA-1237069 (Reactome)
SLC4A1 dimermim-catalysisR-HSA-1237038 (Reactome)
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