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.
Tibell L, Forsman C, Simonsson I, Lindskog S.; ''Anion inhibition of CO2 hydration catalyzed by human carbonic anhydrase II. Mechanistic implications.''; PubMedEurope PMCScholia
Morrow JS, Matthew JB, Wittebort RJ, Gurd FR.; ''Carbon 13 resonances of 13CO2 carbamino adducts of alpha and beta chains in human adult hemoglobin.''; PubMedEurope PMCScholia
Khalifah RG.; ''The carbon dioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic studies on the native human isoenzymes B and C.''; PubMedEurope PMCScholia
Musa-Aziz R, Chen LM, Pelletier MF, Boron WF.; ''Relative CO2/NH3 selectivities of AQP1, AQP4, AQP5, AmtB, and RhAG.''; PubMedEurope PMCScholia
Simonsson I, Jonsson BH, Lindskog S.; ''A 13C nuclear magnetic resonance study of CO2/HCO-3 exchange catalyzed by human carbonic anhydrase I.''; PubMedEurope PMCScholia
Boron WF.; ''Evaluating the role of carbonic anhydrases in the transport of HCO3--related species.''; PubMedEurope PMCScholia
Kwant G, Oeseburg B, Zwart A, Zijlstra WG.; ''Human whole-blood O2 affinity: effect of CO2.''; PubMedEurope PMCScholia
Wistrand PJ, Carter ND, Conroy CW, Mahieu I.; ''Carbonic anhydrase IV activity is localized on the exterior surface of human erythrocytes.''; PubMedEurope PMCScholia
Knauf PA, Gasbjerg PK, Brahm J.; ''The asymmetry of chloride transport at 38 degrees C in human red blood cell membranes.''; PubMedEurope PMCScholia
Bauer C, Schröder E.; ''Carbamino compounds of haemoglobin in human adult and foetal blood.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Ghannam AF, Tsen W, Rowlett RS.; ''Activation parameters for the carbonic anhydrase II-catalyzed hydration of CO2.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Nakhoul NL, Davis BA, Romero MF, Boron WF.; ''Effect of expressing the water channel aquaporin-1 on the CO2 permeability of Xenopus oocytes.''; PubMedEurope PMCScholia
Jensen FB.; ''Red blood cell pH, the Bohr effect, and other oxygenation-linked phenomena in blood O2 and CO2 transport.''; PubMedEurope PMCScholia
Zhu XL, Sly WS.; ''Carbonic anhydrase IV from human lung. Purification, characterization, and comparison with membrane carbonic anhydrase from human kidney.''; PubMedEurope PMCScholia
Geers C, Gros G.; ''Carbon dioxide transport and carbonic anhydrase in blood and muscle.''; PubMedEurope PMCScholia
Baird TT, Waheed A, Okuyama T, Sly WS, Fierke CA.; ''Catalysis and inhibition of human carbonic anhydrase IV.''; PubMedEurope PMCScholia
Acharya AS, Bobelis DJ, White SP.; ''Electrostatic modification at the amino termini of hemoglobin A.''; PubMedEurope PMCScholia
Pesando JM.; ''Proton magnetic resonance studies of carbonic anhydrase. II. Group controlling catalytic activity.''; PubMedEurope PMCScholia
Endeward V, Cartron JP, Ripoche P, Gros G.; ''RhAG protein of the Rhesus complex is a CO2 channel in the human red cell membrane.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Ren X, Lindskog S.; ''Buffer dependence of CO2 hydration catalyzed by human carbonic anhydrase I.''; PubMedEurope PMCScholia
Okuyama T, Sato S, Zhu XL, Waheed A, Sly WS.; ''Human carbonic anhydrase IV: cDNA cloning, sequence comparison, and expression in COS cell membranes.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Morrow JS, Keim P, Visscher RB, Marshall RC, Gurd FR.; ''Interaction of 13 CO 2 and bicarbonate with human hemoglobin preparations.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Blank ME, Ehmke H.; ''Aquaporin-1 and HCO3(-)-Cl- transporter-mediated transport of CO2 across the human erythrocyte membrane.''; PubMedEurope PMCScholia
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).''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Ferguson JK, Roughton FJ.; ''The chemical relationships and physiological importance of carbamino compounds of CO(2) with haemoglobin.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
de Groot BL, Engel A, Grubmüller H.; ''A refined structure of human aquaporin-1.''; PubMedEurope PMCScholia
Sterling D, Reithmeier RA, Casey JR.; ''A transport metabolon. Functional interaction of carbonic anhydrase II and chloride/bicarbonate exchangers.''; PubMedEurope PMCScholia
Forster RE, Constantine HP, Craw MR, Rotman HH, Klocke RA.; ''Reaction of CO2 with human hemoglobin solution.''; PubMedEurope PMCScholia
Murata K, Mitsuoka K, Hirai T, Walz T, Agre P, Heymann JB, Engel A, Fujiyoshi Y.; ''Structural determinants of water permeation through aquaporin-1.''; PubMedEurope PMCScholia
Taylor AM, Boulter J, Harding SE, Cölfen H, Watts A.; ''Hydrodynamic properties of human erythrocyte band 3 solubilized in reduced Triton X-100.''; PubMedEurope PMCScholia
Pinder JC, Pekrun A, Maggs AM, Brain AP, Gratzer WB.; ''Association state of human red blood cell band 3 and its interaction with ankyrin.''; PubMedEurope PMCScholia
Salhany JM, Cordes KA, Sloan RL.; ''Gel filtration chromatographic studies of the isolated membrane domain of band 3.''; PubMedEurope PMCScholia
Dash RK, Bassingthwaighte JB.; ''Erratum to: Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels.''; PubMedEurope PMCScholia
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.
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.
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).
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).
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).
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.
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.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1237044
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
Annotated Interactions