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Oxygen Transport by Hemoglobin

Heimo Mairbäurl, Roy E. Weber

10.1002/cphy.c080113

Source: Volume 2, Issue 2, April 2012

Published online: April 2012

Full Article on Wiley Online Library



Abstract

Hemoglobin (Hb) constitutes a vital link between ambient O2 availability and aerobic metabolism by transporting oxygen (O2) from the respiratory surfaces of the lungs or gills to the O2‐consuming tissues. The amount of O2 available to tissues depends on the blood‐perfusion rate, as well as the arterio‐venous difference in blood O2 contents, which is determined by the respective loading and unloading O2 tensions and Hb‐O2‐affinity. Short‐term adjustments in tissue oxygen delivery in response to decreased O2 supply or increased O2 demand (under exercise, hypoxia at high altitude, cardiovascular disease, and ischemia) are mediated by metabolically induced changes in the red cell levels of allosteric effectors such as protons (H+), carbon dioxide (CO2), organic phosphates, and chloride (Cl−) that modulate Hb‐O2 affinity. The long‐term, genetically coded adaptations in oxygen transport encountered in animals that permanently are subjected to low environmental O2 tensions commonly result from changes in the molecular structure of Hb, notably amino acid exchanges that alter Hb's intrinsic O2 affinity or its sensitivity to allosteric effectors. Structure‐function studies of animal Hbs and human Hb mutants illustrate the different strategies for adjusting Hb‐O2 affinity and optimizing tissue oxygen supply. © 2012 American Physiological Society. Compr Physiol 2:1463‐1489, 2012.

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Figure 1. Figure 1.

Schematic representation of factors that modify O2 transport by hemoglobin in blood. Modified, with permission, after Bouverot 44. See text for details.
Figure 2. Figure 2.

Tetrameric human Hb A, showing two α‐chains in red, two β‐chains in blue, and the iron‐containing heme groups in green. Adapted, with permission, from the Protein Data Bank, 1gzx.
Figure 3. Figure 3.

(A) The globin fold typically seen in mammals (a “three‐over‐three α‐helical sandwich” shown in two colors) composed of helices A to H. (B) The heme (in red), the proximal and distal sites defined by E‐ and F‐helices together with key residues PheCD1, HisE7, and HisF8. Red dashed line, the Fe coordination bonds with the proximal HisF8 residue and liganded O2. The Fe atom is shown in purple, and the hydrogen bond between O2, and the distal HisE7 residue is indicated in blue. Adapted, with permission, from Pesce et al. 167.
Figure 4. Figure 4.

Oxygen dissociation curves (ODCs) for myglobin (Mb), stripped Hb in buffered solution (HbS), and intact human RBCs in whole blood (HbWB). The curve for monomeric Mb is based on P50 = 2.8 mmHg and n = 1 (no cooperativity) and is hyperbolic. The ODC for Hbs (P50 = 5.8 mmHg) and HbWB (P50 = 26.8 mmHg) are cooperative (n50 ∼ 2.5) and thus sigmoidal. The shift to the right of the ODC of HbWB relative to the ODC of HbS is predominantly due to binding of allosteric effectors, which reduce O2 affinity. The inset shows Hill plots for Mb, HbS, and HbWB as well as the affinity constants for the T‐state (KT) and the R‐state (KR) of HbS. Effectors typically reduce KT without significantly affecting KR 251.
Figure 5. Figure 5.

View into the central cavity of the tetrameric Hb molecule, showing the two α‐chains (pink, in background) and the seven positively charged amino acid residues of the two β‐chains (blue‐green) where polyanionic 2,3‐diphosphoglycerate (DPG) binds. DPG binding is reduced in fetal Hbs and in camelid Hb where positively charged residues are replaced by neutral ones (His β 143→Ser and His β 2→Asn, respectively). The image is kindly provided by Dr. Jeremy Tame, Yokohama City University, Japan.
Figure 6. Figure 6.

Effect of 2,3‐diphosphoglycerate (DPG) on Hb‐O2 affinity. Oxygen‐dissociation curves of intact human RBCs after in vitro alteration of the intracellular organic phosphate concentration. Conditions: extracellular pH, 7.4; PCO2, 40 mmHg; temperature, 37°C [adapted, with permission, from Duhm 77].
Figure 7. Figure 7.

Formation of 2,3‐diphosphoglycerate (DPG) in RBC glycolysis. F‐1,6‐P, fructose‐1,6‐diphosphate; 1,3‐DPG, 1,3‐diphosphoglycerate; DPG, 2,3‐diphosphoglycerate; 3‐PG, 3‐phosphoglycerate; PEP, phosphoenolpyruvate; PFK, phosphofructokinase; DPGM, diphosphoglycerate mutase; DPGP, diphosphoglycerate phosphatase. Arrows indicate downward reactions of glycolysis only, intermediate steps are not shown.
Figure 8. Figure 8.

Effects of increased and decreased Hb‐O2 affinity on arterial loading and capillary unloading of oxygen. Oxygen‐dissociation curves (ODCs) refer to arterial (three curves at Po2 > 35 mmHg) and capillary blood (Po2 < 33 mmHg). The continuous line represents a normal ODC with a “standard” P50 of 26.8 mmHg for arterial blood [calculated according to reference 206]. The leftward‐ and rightward‐shifted ODCs are calculated from pH shifts of ±0.1 resulting in P50 values of 24 and 30 mmHg, respectively. The ODCs for capillary blood are right‐shifted relative to those of arterial blood due to the more acidic environment in the capillary (ΔpH = −0.1). A Bohr coefficient of −0.48 was used for calculations. Long vertical arrows indicate the percent O2 unloaded from Hb assuming arterial Po2 = 90 and 45 mmHg and capillary Po2 = 30 and 15 mmHg in normoxia and hypoxia, respectively, as indicated by the short continuous (normoxia) and broken (hypoxia) arrows on the Po2 axis. The slopes of the diagonal arrows (that only are drawn for the normoxic condition) indicate the capacitance “β” that is the driving force for O2 unloading. The resulting values for arterial and capillary SO2 and the effects on unloading of O2 from Hb are summarized in Table 3. See text for further details.
Figure 9. Figure 9.

Blood P50 values of mammalian Hbs as a function of body weight. The P50 values of blood samples of mammals ranging in body mass from 21 g to 635 kg were determined at 37°C and at PCO2 = 40 mmHg [adapted, with permission, from Schmidt‐Nielsen and Larimer 204].
Figure 10. Figure 10.

Change in the expression of human globin genes during embryonic, fetal, and postnatal development [modified, with permission, After Wood 271 and Schechter 202]. The figure shows that the embryonic Hbs Gower I (ζ2ɛ2), Gower II (α2ɛ2), and Portland (ζ2γ2) are predominantly expressed within the first 6 weeks of intrauterine life, that fetal Hb (α2γ2) predominates from a about 3 weeks after conception until about 3 weeks after birth, and that adult Hb (α2β2) increases strongly around birth.
Figure 11. Figure 11.

Oxygen‐dissociation curves (ODCs) of stripped human adult and fetal Hbs (A and F, respectively) in the absence (DPG/Hb = 0) and presence (DPG/Hb = 1) of equimolar concentrations of 2,3 diphosphoglycerate at 20°C and pH 7.2 (the approximate intracellular pH value). Inset: ODCs for maternal (continuous curve) and fetal (broken curve) human blood at 37°C and pH 7.4, illustrating arterio‐venous content differences (double arrows) and higher O2 affinity and O2‐carrying capacity in fetal blood [adapted, with permission, from 225,245].
Figure 12. Figure 12.

Effects of exercise on Hb‐O2 affinity O2‐dissociation curves (ODC) and their shifts are calculated on arterial pH = 7.4 and temperature of 37°C at rest, and the changes of blood gases induced by exercise indicated in the table as reported by Sun et al. 218 using the formulas reported by Severinghaus 206. Acid‐base and temperature differences between arterial and capillary blood cause a rest increase P50‐values from 26 mmHg in arterial blood to 30 mmHg in capillary blood. During exercise capillary blood P50‐value increases ∼49 mmHg. The difference in SO2 at the pulmonary venous PO2 at rest (Pv,r) and during exercise (Pv,e) and SO2 in venous blood leaving the exercising muscle at rest (Mv,r) and during exercise (Mv,e) is 28% at rest but 79% during exercise indicating a 2.8‐fold increase in the amount of O2 unloaded from Hb. Pa, Pv, and Ma, Mv indicate pulmonary and muscular arterial and venous blood, respectively, and the indices “r” and “e” denote to rest and exercise. Temp. is the temperature in the respective blood in °C, pH is the plasma pH (likely changes in intra‐erythrocytic pH are difficult to estimate and are thus not accounted for). PCO2 is the CO2 partial pressure (mmHg).


Figure 1.

Schematic representation of factors that modify O2 transport by hemoglobin in blood. Modified, with permission, after Bouverot 44. See text for details.



Figure 2.

Tetrameric human Hb A, showing two α‐chains in red, two β‐chains in blue, and the iron‐containing heme groups in green. Adapted, with permission, from the Protein Data Bank, 1gzx.



Figure 3.

(A) The globin fold typically seen in mammals (a “three‐over‐three α‐helical sandwich” shown in two colors) composed of helices A to H. (B) The heme (in red), the proximal and distal sites defined by E‐ and F‐helices together with key residues PheCD1, HisE7, and HisF8. Red dashed line, the Fe coordination bonds with the proximal HisF8 residue and liganded O2. The Fe atom is shown in purple, and the hydrogen bond between O2, and the distal HisE7 residue is indicated in blue. Adapted, with permission, from Pesce et al. 167.



Figure 4.

Oxygen dissociation curves (ODCs) for myglobin (Mb), stripped Hb in buffered solution (HbS), and intact human RBCs in whole blood (HbWB). The curve for monomeric Mb is based on P50 = 2.8 mmHg and n = 1 (no cooperativity) and is hyperbolic. The ODC for Hbs (P50 = 5.8 mmHg) and HbWB (P50 = 26.8 mmHg) are cooperative (n50 ∼ 2.5) and thus sigmoidal. The shift to the right of the ODC of HbWB relative to the ODC of HbS is predominantly due to binding of allosteric effectors, which reduce O2 affinity. The inset shows Hill plots for Mb, HbS, and HbWB as well as the affinity constants for the T‐state (KT) and the R‐state (KR) of HbS. Effectors typically reduce KT without significantly affecting KR 251.



Figure 5.

View into the central cavity of the tetrameric Hb molecule, showing the two α‐chains (pink, in background) and the seven positively charged amino acid residues of the two β‐chains (blue‐green) where polyanionic 2,3‐diphosphoglycerate (DPG) binds. DPG binding is reduced in fetal Hbs and in camelid Hb where positively charged residues are replaced by neutral ones (His β 143→Ser and His β 2→Asn, respectively). The image is kindly provided by Dr. Jeremy Tame, Yokohama City University, Japan.



Figure 6.

Effect of 2,3‐diphosphoglycerate (DPG) on Hb‐O2 affinity. Oxygen‐dissociation curves of intact human RBCs after in vitro alteration of the intracellular organic phosphate concentration. Conditions: extracellular pH, 7.4; PCO2, 40 mmHg; temperature, 37°C [adapted, with permission, from Duhm 77].



Figure 7.

Formation of 2,3‐diphosphoglycerate (DPG) in RBC glycolysis. F‐1,6‐P, fructose‐1,6‐diphosphate; 1,3‐DPG, 1,3‐diphosphoglycerate; DPG, 2,3‐diphosphoglycerate; 3‐PG, 3‐phosphoglycerate; PEP, phosphoenolpyruvate; PFK, phosphofructokinase; DPGM, diphosphoglycerate mutase; DPGP, diphosphoglycerate phosphatase. Arrows indicate downward reactions of glycolysis only, intermediate steps are not shown.



Figure 8.

Effects of increased and decreased Hb‐O2 affinity on arterial loading and capillary unloading of oxygen. Oxygen‐dissociation curves (ODCs) refer to arterial (three curves at Po2 > 35 mmHg) and capillary blood (Po2 < 33 mmHg). The continuous line represents a normal ODC with a “standard” P50 of 26.8 mmHg for arterial blood [calculated according to reference 206]. The leftward‐ and rightward‐shifted ODCs are calculated from pH shifts of ±0.1 resulting in P50 values of 24 and 30 mmHg, respectively. The ODCs for capillary blood are right‐shifted relative to those of arterial blood due to the more acidic environment in the capillary (ΔpH = −0.1). A Bohr coefficient of −0.48 was used for calculations. Long vertical arrows indicate the percent O2 unloaded from Hb assuming arterial Po2 = 90 and 45 mmHg and capillary Po2 = 30 and 15 mmHg in normoxia and hypoxia, respectively, as indicated by the short continuous (normoxia) and broken (hypoxia) arrows on the Po2 axis. The slopes of the diagonal arrows (that only are drawn for the normoxic condition) indicate the capacitance “β” that is the driving force for O2 unloading. The resulting values for arterial and capillary SO2 and the effects on unloading of O2 from Hb are summarized in Table 3. See text for further details.



Figure 9.

Blood P50 values of mammalian Hbs as a function of body weight. The P50 values of blood samples of mammals ranging in body mass from 21 g to 635 kg were determined at 37°C and at PCO2 = 40 mmHg [adapted, with permission, from Schmidt‐Nielsen and Larimer 204].



Figure 10.

Change in the expression of human globin genes during embryonic, fetal, and postnatal development [modified, with permission, After Wood 271 and Schechter 202]. The figure shows that the embryonic Hbs Gower I (ζ2ɛ2), Gower II (α2ɛ2), and Portland (ζ2γ2) are predominantly expressed within the first 6 weeks of intrauterine life, that fetal Hb (α2γ2) predominates from a about 3 weeks after conception until about 3 weeks after birth, and that adult Hb (α2β2) increases strongly around birth.



Figure 11.

Oxygen‐dissociation curves (ODCs) of stripped human adult and fetal Hbs (A and F, respectively) in the absence (DPG/Hb = 0) and presence (DPG/Hb = 1) of equimolar concentrations of 2,3 diphosphoglycerate at 20°C and pH 7.2 (the approximate intracellular pH value). Inset: ODCs for maternal (continuous curve) and fetal (broken curve) human blood at 37°C and pH 7.4, illustrating arterio‐venous content differences (double arrows) and higher O2 affinity and O2‐carrying capacity in fetal blood [adapted, with permission, from 225,245].



Figure 12.

Effects of exercise on Hb‐O2 affinity O2‐dissociation curves (ODC) and their shifts are calculated on arterial pH = 7.4 and temperature of 37°C at rest, and the changes of blood gases induced by exercise indicated in the table as reported by Sun et al. 218 using the formulas reported by Severinghaus 206. Acid‐base and temperature differences between arterial and capillary blood cause a rest increase P50‐values from 26 mmHg in arterial blood to 30 mmHg in capillary blood. During exercise capillary blood P50‐value increases ∼49 mmHg. The difference in SO2 at the pulmonary venous PO2 at rest (Pv,r) and during exercise (Pv,e) and SO2 in venous blood leaving the exercising muscle at rest (Mv,r) and during exercise (Mv,e) is 28% at rest but 79% during exercise indicating a 2.8‐fold increase in the amount of O2 unloaded from Hb. Pa, Pv, and Ma, Mv indicate pulmonary and muscular arterial and venous blood, respectively, and the indices “r” and “e” denote to rest and exercise. Temp. is the temperature in the respective blood in °C, pH is the plasma pH (likely changes in intra‐erythrocytic pH are difficult to estimate and are thus not accounted for). PCO2 is the CO2 partial pressure (mmHg).

References
 1. Aberman A, Cavanilles JM, Weil MH, Shubin H. Blood P50 calculated from single measurements of pH, PO2, and SO2. J Appl Physiol 38: 171‐176, 1975.
 2. Adair GS. The hemoglobin system. VI. The oxygen dissociation curve of hemoglobin. J Biol Chem 63: 529‐545, 1925.
 3. Amiconi G, Antonini E, Brunori M, Wyman J, Zolla L. Interaction of hemoglobin with salts. Effects on the functional properties of human hemoglobin. J Mol Biol 152: 111‐129, 1981.
 4. Amiconi G, Bertollini A, Bellelli A, Coletta M, Condo SG, Brunori M. Evidence for two oxygen‐linked binding sites for polyanions in dromedary hemoglobin. Eur J Biochem 150: 387‐393, 1985.
 5. Antonini E, Schuster TD, Brunori M, Wyman J. The kinetics of the Bohr effect in the reaction of human hemoglobin with carbon monoxide. J Biol Chem 240: 2262‐2264, 1965.
 6. Arnone A. X‐ray diffraction study of binding of 2,3‐diphosphoglycerate to human deoxyhaemoglobin. Nature 237: 146‐149, 1972.
 7. Arnone A. Mechanism of action of hemoglobin. Annu Rev Med 25: 123‐130, 1974a.
 8. Arnone A. X‐ray studies of the interaction of CO2 with human deoxyhaemoglobin. Nature 247: 143‐145, 1974b.
 9. Atha DH, Ackers GK. Calorimetric determination of the heat of oxygenation of human hemoglobin as a function of pH and the extent of reaction. Biochem 13(11): 2376‐2382, 1974.
 10. Bailey JE, Beetlestone JG, Irvine DH. Reactivity differences between hemoglobins. XVII. The variability of the Bohr effect between species and the effect of 2,3‐diphosphoglycerate on the Bohr effect. J Chem Soc A 5: 756‐762, 1970.
 11. Barcroft J, King WO. The effect of temperature on the dissociation curve of blood. J Physiol 39: 374‐384, 1909.
 12. Bartlett GR. Phosphate compounds in rat erythrocytes and reticulocytes. Biochem Biophys Res Commun 70/4: 1055‐1062, 1976.
 13. Bartlett GR. Phosphate compounds in red cells of reptiles, amphibians and fish. Comp Biochem Physiol A Comp Physiol 55: 211‐214, 1976.
 14. Bartlett GR, Borgese TA. Phosphate compounds in red cells of the chicken and duck embryo and hatchling. Comp Biochem Physiol A Comp Physiol 55: 207‐210, 1976.
 15. Barvitenko NN, Adragna NC, Weber RE. Erythrocyte signal transduction pathways, their oxygenation dependence and functional significance. Cell Physiol Biochem 15: 1‐18, 2005.
 16. Bauer C. Antagonistic influence of CO2 and 2,3‐diphosphoglycerate on the Bohr effect of human haemoglobin. Life Sci 8: 1041‐1046, 1969.
 17. Bauer C. Reduction of the carbon dioxide affinity of human haemoglobin solutions by 2,3‐diphosphoglycerate. Respir Physiol 10: 10‐19, 1970.
 18. Bauer C, Baumann R, Engels U, Pacyna B. The carbon dioxide affinity of various human hemoglobins. J Biol Chem 250: 2173‐2176, 1975.
 19. Bauer C, Rollema HS, Till HW, Braunitzer G. Phosphate binding by llama and camel hemoglobin. J Comp Physiol 136: 67‐70, 1980.
 20. Bauman R, Bauer C, Haller EA. Oxygen‐linked CO2 transport in sheep blood. Am J Physiol 229: 334‐339, 1975.
 21. Baumann FH, Baumann R. A comparative study of the respiratory properties of bird blood. Respir Physiol 31: 333‐343, 1977.
 22. Baumann R, Haller EA. Cat haemoglobins A and B: Differences in the interaction with Cl minus, phosphate and CO2. Biochem Biophys Res Commun 65: 220‐227, 1975.
 23. Beall CM. Andean, Tibetan, and Ethiopian patterns of adaptation to high‐altitude hypoxia. Integr Comp Biol 46: 18‐24, 2006.
 24. Bellingham AJ. The physiological significance of the Hill parameter ‘n’. Scand J Haematol 9: 552‐556, 1972.
 25. Bellingham AJ. Haemoglobins with altered oxygen affinity. Br Med Bull 32: 234‐238, 1976.
 26. Benesch R, Benesch RE. The effect of organic phosphates from human erythrocytes on the allosteric properties of hemoglobin. Biochem Biophys Res Commun 26: 162‐167, 1967.
 27. Benesch R, Benesch RE, Yu CI. Reciprocal binding of oxygen and diphosphoglycerate by human hemoglobin. Proc Natl Acad Sci U S A 59: 526‐532, 1968.
 28. Benesch RE, Benesch R, Yu CI. The oxygenation of hemoglobin in the presence of 2,3‐diphosphoglycerate. Effect of temperature, pH, ionic strength, and hemoglobin concentration. Biochem 8: 2567‐2571, 1969.
 29. Berenbrink M. Evolution of vertebrate haemoglobins: Histidine side chains, specific buffer value and Bohr effect. Respir Physiol Neurobiol 154: 165‐184, 2006.
 30. Berlin G, Challoner KE, Woodson RD. Low‐O2 affinity erythrocytes improve performance of ischemic myocardium. J Appl Physiol 92: 1267‐1276, 2002.
 31. Bert P. La Pression Barometrique. Paris: Masson, 1878.
 32. Beutler E. Red Cell Metabolism: A Manual of Biochemical Methods. New York: Grune & Stratton, 1975.
 33. Blunt MH, Kitchens JL, Mayson SM, Huisman TH. Red cell 2,3‐diphosphoglycerate and oxygen affinity in newborn goats and sheep. Proc Soc Exp Biol Med 138: 800‐803, 1971.
 34. Bohr C. Die Sauerstoffaufnahme des genuinen Blutfarbstoffs und des aus dem Blute dargestellten Hämoglobins. Zbl Physiol 17: 688‐691, 1903.
 35. Bohr C, Hasselbalch K, Krogh A. Über einen in biologischer Beziehung wichtigen Einfluß, den die Kohlensäurespannung des Blutes auf dessen Sauerstoffspannung ausübt. Scand Arch Physiol 16: 402‐412, 1904.
 36. Bonaventura C, Bonaventura J. Competition in oxygen‐linked anion binding to normal and variant human hemoglobins. Hemoglobin 4: 275‐289, 1980.
 37. Bonaventura C, Crumbliss AL, Weber RE. New insights into the proton‐dependent oxygen affinity of Root effect haemoglobins. Acta Physiol Scand 182: 245‐258, 2004.
 38. Bonaventura C, Ferruzzi G, Tesh S, Stevens RD. Effects of S‐nitrosation on oxygen binding by normal and sickle cell hemoglobin. J Biol Chem 274: 24742‐24748, 1999.
 39. Bonaventura J, Riggs A. Hemoglobin Kansas, a human hemoglobin with a neutral amino acid substitution and an abnormal oxygen equilibrium. J Biol Chem 243: 980‐991, 1968.
 40. Böning D, Enciso G. Hemoglobin‐oxygen affinity in anemia. Blut 54: 361‐368, 1987.
 41. Böning D, Schweigart U, Tibes U, Hemmer B. Influences of exercise and endurance training on the oxygen dissociation curve of blood under in vivo and in vitro conditions. Eur J Appl Physiol 34: 1‐10, 1975.
 42. Böning D, Trost F, Braumann KM, Bitter H, Bender K, Mühlen A, Schweigart U. Altitude acclimatization in skiing lowlanders. Int J Sports Med 1: 191‐198, 1980.
 43. Borgese F, Garcia‐Romeu F, Motais R. Catecholamine‐induced transport systems in trout erythrocyte: Na+/H+ countertransport or NaCl cotransport? J Gen Physiol 87: 551‐566, 1986.
 44. Bouverot P. Adaptation to Altitude Hypoxia in Vertebrates. Berlin: Springer Verlag, 1985.
 45. Braumann KM, Böning D, Trost F. Bohr effect and slope of the oxygen dissociation curve after physical training. J Appl Physiol 52: 1524‐1529, 1982.
 46. Braunitzer G, Hilse K, Rudloff V, Hilschmann N. The hemoglobins. Adv Protein Chem 19: 1‐71, 1964.
 47. Brewer GJ, Eaton JW. Erythrocyte metabolism: Interactions with oxygen transport. Science 171: 1205‐1211, 1971.
 48. Brittain T. Molecular aspects of embryonic hemoglobin function. Mol Aspects Med 23: 293‐342, 2002.
 49. Brittain T, Wells RMG. Oxygen transport in early mammalian development: Molecular physiology of embryonic hemoglobins. In: Johnson MH, editor. Development in Mammals, Vol. 5. Amsterdam: Elsevier Science Publishers, 1983, p. 135‐154.
 50. Brooks J. The action of nitrite on haemoglobin in the absence of oxygen. Proc Roy Soc B 123: 368‐382, 1937.
 51. Brown EG, Krouskop RW, McDonnell FE, Monge CC, Winslow RM. A technique to continuously measure arteriovenous oxygen content and P50 in vivo. J Appl Physiol 58/4: 1383‐1389, 1985.
 52. Brown WEL, Hill AV. The oxygen dissociation curve of blood, and its thermodynamical basis. Proc Roy Soc B 94: 297‐334, 1923.
 53. Brunet P, Berland Y, Merzouk T, Vanuxem D, Badier M, Klinkmann H, Crevat A. Effect of recombinant human erythropoietin treatment in uremic patients on oxygen affinity of hemoglobin. Nephron 66: 147‐152, 1994.
 54. Brygier J, de Bruin SH, Van Hoof MK, Rollema HS. The interaction of organic phosphates with human and chicken hemoglobin. Eur J Biochem 60: 379‐383, 1975.
 55. Bunn HF. Regulation of hemoglobin function in mammals. Am Zool 20: 199‐211, 1980.
 56. Bunn HF, Forget BG, Ranney HM. Human Hemoglobins. Philadelphia: Saunders, 1977.
 57. Bunn HF, Ransil BJ, Chao A. The interaction between erythrocyte organic phosphates, magnesium ion, and hemoglobin. J Biol Chem 246/17: 5273‐5279, 1971.
 58. Burmester T, Haberkamp M, Mitz S, Roesner A, Schmidt M, Ebner B, Gerlach F, Fuchs C, Hankeln T. Neuroglobin and cytoglobin: Genes, proteins and evolution. Iubmb Life 56: 703‐707, 2004.
 59. Cabantchik ZI. Erythrocyte membrane transport. Novartis Found Symp 226: 6‐16, 1999.
 60. Campbell KL, Roberts JE, Watson LN, Stetefeld J, Sloan AM, Signore AV, Howatt JW, Tame JR, Rohland N, Shen TJ, Austin JJ, Hofreiter M, Ho C, Weber RE, Cooper A. Substitutions in woolly mammoth hemoglobin confer biochemical properties adaptive for cold tolerance. Nat Genet 42: 536‐540, 2010.
 61. Campbell KL, Storz JF, Signore AV, Moriyama H, Catania KC, Payson AP, Bonaventura J, Stetefeld J, Weber RE. Molecular basis of a novel adaptation to hypoxic‐hypercapnia in a strictly fossorial mole. BMC Evol Biol 10: 214, 2010.
 62. Carroll SB. The Making of the Fittest. New York: Norton & Company, 2007.
 63. Cerretelli P, DiPrampero PE. Aerobic and anaerobic metabolism during exercise at altitude. In: Rivolier J, Cerretelli P, Foray J, Segantini P, editors. High Altitude Deterioration. Basel: Karger, 1985, p. 1‐19.
 64. Chanutin A, Curnish RR. Effects of organic and inorganic phosphates on the oxygen equilibrium of human erythrocytes. Arch Biochem Biophys 121: 96‐102, 1967.
 65. Chiancone E, Norne JE, Forsen S, Antonini E, Wyman J. Nuclear magnetic resonance quadrupole relaxation studies of chloride binding to human oxy‐ and deoxyhaemoglobin. J Molecular Biology 70: 675‐688, 1972.
 66. Christiansen J, Douglas CG, Haldane JS. The absorption and dissociation of carbon dioxide by human blood. J Physiol 48: 244‐271, 1914.
 67. Chu H, Breite A, Ciraolo P, Franco RS, Low PS. Characterization of the deoxyhemoglobin binding site on human erythrocyte band 3: Implications for O2 regulation of erythrocyte properties. Blood 111: 932‐938, 2008.
 68. Coletta M, Clementi ME, Ascenzi P, Petruzzelli R, Condo SG, Giardina B. A comparative study of the temperature dependence of the oxygen‐binding properties of mammalian hemoglobins. Eur J Biochem 204: 1155‐1157, 1992.
 69. Colombo MF, Seixas FAV. Novel allosteric conformation of human Hb revealed by the hydration and anion effects on O2 binding. Biochem 38: 11741‐11748, 1999.
 70. De Rosa MC, Castagnola M, Bertonati C, Galtieri A, Giardina B. From the Arctic to fetal life: Physiological importance and structural basis of an ‘additional’ chloride‐binding site in haemoglobin. Biochem J 380: 889‐896, 2004.
 71. Dempsey JA, Wagner PD. Exercise‐induced arterial hypoxemia. J Appl Physiol 87: 1997‐2006, 1999.
 72. Di Cera E, Doyle ML, Morgan MS, De Cristofaro R, Landolfi R, Bizzi B, Castagnola M, Gill SJ. Carbon monoxide and oxygen binding to human hemoglobin F0. Biochem 28: 2631‐2638, 1989.
 73. Dickerson RE, Geis I. Hemoglobin: Structure, Function, Evolution, and Pathology. Menlo Park: Cummings Publishing, 1983.
 74. Dill DB, Forbes WH. Respiratory and metabolic effects of hypothermia. Am J Physiol 132: 685‐697, 1941.
 75. Douglas CB, Haldane JS, Haldane JBS. The laws of combination of hemoglobin with carbon monoxide and oxygen. J Physiol (London) 44: 275‐304, 1912.
 76. Dubinsky WP, Racker E. The mechanism of lactate transport in human erythrocytes. J Membrane Biol 44: 25‐36, 1978.
 77. Duhm J. Effects of 2,3‐Diphosphoglycerate and other organic phosphate compounds on oxygen affinity and intracellular pH of human erythrocytes. Pflügers Arch Eur J Physiol 326: 341‐356, 1971a.
 78. Duhm J. On the mechanisms of the hypoxia‐induced increase of 2,3‐diphosphoglycerate in erythrocytes. Pflügers Arch Eur J Physiol 326: 254‐269, 1971b.
 79. Duhm J. Dual effect of 2,3‐diphosphoglycerate on the Bohr effects of human blood. Pflügers Arch Eur J Physiol 363: 55‐60, 1976.
 80. Duvelleroy MA, Buckles RG, Rosenkaimer S, Tung C, Laver MB. An oxyhemoglobin dissociation analyzer. J Appl Physiol 28: 227‐233, 1970.
 81. Eaton JW, Skelton TD, Berger E. Survival at extreme altitude: Protective effect of increased hemoglobin‐oxygen affinity. Science 183: 743‐744, 1974.
 82. Eckardt KU, Boutellier U, Kurtz A, Schopen M, Koller EA, Bauer C. Rate of erythropoietin formation in humans in response to acute hypobaric hypoxia. J Appl Physiol 66: 1785‐1788, 1989.
 83. Fago A, Bendixen E, Malte H, Weber RE. The anodic hemoglobin of Anguilla anguilla. Molecular basis for allosteric effects in a Root‐effect hemoglobin. J Biol Chem 272: 15628‐15635, 1997.
 84. Fermi G. Three‐dimensional Fourier synthesis of human deoxyhaemoglobin at 2‐5 A resolution: Refinement of the atomic model. J Mol Biol 97: 237‐256, 1975.
 85. Fermi G, Perutz MF. Atlas of Molecular Structures in Biology. 2. Hemoglobin and Myoglobin. Oxford: Clarendon Press, 1981.
 86. Frier JA, Perutz MF. Structure of human foetal deoxyhaemoglobin. J Mol Biol 112: 97‐112, 1977.
 87. Funder J, Wieth JO. Chloride and hydrogen ion distribution between human red cells and plasma. Acta Physiol Scand 68: 234‐245, 1966.
 88. Garby L, Robert M, Zaar B. Proton‐ and carbamino‐linked oxygen affinity of normal human blood. Acta Physiol Scand 84: 482‐492, 1972.
 89. Giardina B, Mosca D, De Rosa MC. The Bohr effect of haemoglobin in vertebrates: An example of molecular adaptation to different physiological requirements. Acta Physiol Scand 182: 229‐244, 2004.
 90. Gibson WH, Roughton FJ. The kinetics and equilibria of the reactions of nitric oxide with sheep haemoglobin. J Physiol 136: 507‐524, 1957.
 91. Gladwin MT, Kim‐Shapiro DB. The functional nitrite reductase activity of the heme‐globins. Blood 112: 2636‐2647, 2008.
 92. Gow AJ, Stamler JS. Reactions between nitric oxide and haemoglobin under physiological conditions. Nature 391: 169‐173, 1998.
 93. Gray RD. The kinetics of the alkaline Bohr effect of human hemoglobin. J Biol Chem 245: 2914‐2921, 1970.
 94. Grimes AJ. Human Red Cell Metabolism. Oxford: Blackwell Science, 1980.
 95. Gros G, Rollema HS, Forster RE. The carbamate equilibrium of alpha‐ and epsilon‐amino groups of human hemoglobin at 37 degrees C. J Biol Chem 256: 5471‐5480, 1981.
 96. Guesnon P, Poyart C, Bursaux E, Bohn B. The binding of lactate and chloride ions to human adult hemoglobin. Respir Physiol 38: 115‐129, 1979.
 97. Haire RN, Hedlund BE. Thermodynamic aspects of the linkage between binding of chloride and oxygen to human hemoglobin. Proc Natl Acad Sci U S A 74: 4135‐4138, 1977.
 98. Hazard ES, Hutchison VH. Distribution of acid‐soluble phosphates in the erythrocytes of selected species of amphibians. Comp Biochem Physiol A Physiol A73: 111‐124, 1982.
 99. Hebbel RP, Eaton JW, Kronenberg RS, Zanjani ED, Moore LG, Berger EM. Human Llamas. Adaptation to altitude in subjects with high hemoglobin oxygen affinity. J Clin Invest 62: 593‐600, 1978.
 100. Henriques OM. Über Carboxyhämoglobin. Ergeb Physiol Biol Chem Exp Pharmakol 28: 625‐689, 1929.
 101. Hiebl I, Weber RE, Schneeganss D, Kosters J, Braunitzer G. High‐altitude respiration of birds. Structural adaptations in the major and minor hemoglobin components of adult Ruppell's Griffon (Gypus rueppellii, Aegypiinae): A new molecular pattern for hypoxic tolerance. Biol Chem Hoppe Seyler 369: 217‐232, 1988.
 102. Hill AV. The possible effects of aggregation of the molecules of hemoglobin on its dissociation curve. J Physiol (London) 40: iv‐vii, 1910.
 103. Hlastala MP, Woodson RD. Saturation dependency of the Bohr effect: Interactions among H+, CO2, and DPG. J Appl Physiol 38(6): 1126‐1131, 1975.
 104. Hochachka PW. Defense strategies against hypoxia and hypothermia. Science 231: 234‐241, 1986.
 105. Hoffman JF, Laris PC. Determination of membrane potentials in human and amphiuma red blood cells by means of a fluorescent probe. J Physiol (London) 239: 519‐552, 1974.
 106. Horvath SM, Malenfant A, Rossi F, Rossi‐Bernardi L. The oxygen affinity of concentrated human hemoglobin solutions and human blood. Am J Hematol 2: 343‐354, 1977.
 107. Hrinczenko BW, Alayash AI, Wink DA, Gladwin MT, Rodgers GP, Schechter AN. Effect of nitric oxide and nitric oxide donors on red blood cell oxygen transport. Br J Haematol 110: 412‐419, 2000.
 108. Huehns ER, Faroqui AM. Oxygen dissociation properties of human embryonic red cells. Nature 254: 335‐337, 1975.
 109. Humpeler E, Amor H. Sex differences in the oxygen affinity of hemoglobin. Pflügers Arch Eur J Physiol 343: 151‐156, 1973.
 110. Humpeler E, Amor H, Braunsteiner H. Unterschiedliche Sauerstoffaffinität des Hämoglobins bei Anämien unterschiedlicher Ätiologie. Blut 29: 382‐390, 1974.
 111. Humpeler E, Inama K, Deetjen P. Improvement of tissue oxygenation during a 20 days‐stay at moderate altitude in connection with mild exercise. Klin Wochenschr 57: 267‐272, 1979.
 112. Humpeler E, Vogel S. Oxygen affinity of hemoglobin in postmenopausal women. Pflügers Arch Eur J Physiol 372: 287‐288, 1977.
 113. Humpeler E, Vogel S, Schobersberger W, Mairbäurl H. Red cell oxygen transport in relation to sex and age. Mechan Aging Develop 47: 229‐239, 1989.
 114. Hundahl C, Fago A, Malte H, Weber RE. Allosteric effect of water in fish and human hemoglobins. J Biol Chem 278: 42769‐42773, 2003.
 115. Imai K. Analyses of oxygen equilibria of native and chemically modified human adult hemoglobins on the basis of Adair's stepwise oxygenation theory and the allosteric model of Monod, Wyman, and Changeux. Biochem 12: 798‐807, 1973.
 116. Imai K. Allosteric Effects in Haemoglobin. Cambridge: Cambridge University Press, 1982.
 117. Imai K, Yonetani T. pH dependence of the Adair constants of human hemoglobin. Nonuniform contribution of successive oxygen bindings to the alkaline Bohr effect. J Biol Chem 250: 2227‐2231, 1975.
 118. Imaizumi K, Imai K, Tyuma I. The linkage between the four step binding of oxygen and the binding of heterotropic anionic ligands in hemoglobin. J Biochem 86: 1829‐1840, 1979.
 119. Isaacks R, Harkness D, Sampsell R, Adler J, Roth S, Kim C, Goldman P. Studies on avian erythrocyte metabolism. Inositol tetrakisphosphate: The major phosphate compound in the erythrocytes of the ostrich (Struthio camelus camelus). Eur J Biochem 77: 567‐574, 1977.
 120. Isaacks RE, Harkness DR, Goldman PH, Adler JL, Kim CY. Studies on avian erythrocyte metabolism. VII. Effect of inositol pentaphosphate and other organic phosphates on oxygen affinity of the embryonic and adult‐type hemoglobins of the turkey embryo. Hemoglobin 1: 577‐593, 1977.
 121. Jelkmann W, Bauer C. High pyruvate kinase activity causes low concentration of 2,3‐diphosphoglycerate in fetal rabbit red cells. Pflügers Arch Eur J Physiol 375: 189‐195, 1978.
 122. Jelkmann W, Bauer C. 2,3‐DPG levels in relation to red cell enzyme activities in rat fetuses and hypoxic newborns. Pflügers Arch Eur J Physiol 389: 61‐68, 1980.
 123. Jensen FB. Red blood cell pH, the Bohr effect, and other oxygenation‐linked phenomena in blood O2 and CO2 transport. Acta Physiol Scand 182: 215‐227, 2004.
 124. Jensen M, Oski FA, Nathan DG, Bunn HF. Hemoglobin Syracuse (alpha2beta2‐143(H21)His leads to Pro), a new high‐affinity variant detected by special electrophoretic methods. Observations on the auto‐oxidation of normal and variant hemoglobins. J Clin Invest 55: 469‐477, 1975.
 125. Jessen TH, Weber RE, Fermi G, Tame J, Braunitzer G. Adaptation of bird hemoglobins to high altitudes: Demonstration of molecular mechanism by protein engineering. Proc Natl Acad Sci U S A 88: 6519‐6522, 1991.
 126. John WG. Glycated haemoglobin analysis. Ann Clin Biochem 34(Pt 1): 17‐31, 1997.
 127. Joyce BK, Grisolia S. The purification and properties of muscle diphosphoglycerate mutase. J Biol Chem 234: 1330‐1334, 1959.
 128. Keitt AS. Hemolytic anemia with impaired hexokinase activity. J Clin Invest 48: 1997‐2007, 1969.
 129. Kernohan JC, Roughton FJ. The precise determination of the bottom of the oxyhaemoglobin dissociation curve of human blood. In: Rorth M, Astrup P, editors. Oxygen Affinity of Hemoglobin and Red Cell Acid Base Status. Copenhagen: Munksgaard, 1972, p. 54‐64.
 130. Kilmartin JV, Imai K, Jones RT, Faruqui AR, Fogg J, Baldwin JM. Role of Bohr group salt bridges in cooperativity in hemoglobin. Biochim Biophys Acta 534: 15‐25, 1978.
 131. Kilmartin JV, Rossi‐Bernardi L. Interaction of hemoglobin with hydrogen ions, carbon dioxide, and organic phosphates. Physiol Rev 53: 836‐890, 1973.
 132. Larsen C, Malte H, Weber RE. ATP‐induced reverse temperature effect in isohemoglobins from the endothermic porbeagle shark (Lamna pasus). J Biol Chem 278: 30741‐30747, 2003.
 133. Ledingham IM. Factors influencing oxygen availability. J Clin Pathol Suppl (R Coll Pathol) 11: 1‐6, 1977.
 134. Lee YW, Ki CS, Kim HJ, Lee ST, Kim CK, Shin HB, Hong DS, Lee YK. High oxygen‐affinity hemoglobin variant associated with high‐level venous oxygen saturation. Clin Chem Lab Med 46: 417‐418, 2008.
 135. Liang Y, Hua Z, Liang X, Xu Q, Lu G. The crystal structure of bar‐headed goose hemoglobin in deoxy form: The allosteric mechanism of a hemoglobin species with high oxygen affinity. J Mol Biol 313: 123‐137, 2001.
 136. Low PS, Rathinavelu P, Harrison ML. Regulation of glycolysis via reversible enzyme binding to the membrane protein, band‐3. J Biol Chem 268: 14627‐14631, 1993.
 137. Lukin JA, Ho C. The structure‐function relationship of hemoglobin in solution at atomic resolution. Chem Revs 104: 1219‐1230, 2004.
 138. Mairbäurl H. Red blood cell function at high altitude. Ann Sports Med 4(4): 189‐195, 1988.
 139. Mairbäurl H. Red blood cell function in hypoxia at altitude and exercise. Int J Sports Med 15(2): 51‐63, 1994.
 140. Mairbäurl H, Hoffman JF. Internal magnesium, 2,3‐diphosphoglycerate, and the regulation of the steady‐state volume of human red blood cells by the Na/K/2Cl cotransport system. J Gen Physiol 99: 721‐746, 1992.
 141. Mairbäurl H, Humpeler E. Diminution of the temperature effect on the oxygen affinity of hemoglobin after prolonged hypothermia. Pflügers Arch Eur J Physiol 383: 209‐213, 1980.
 142. Mairbäurl H, Humpeler E, Schwaberger G, Pessenhofer H. Training dependent changes of red cell density and erythrocytic oxygen transport. J Appl Physiol 55(5): 1403‐1407, 1983.
 143. Mairbäurl H, Oelz O, Bärtsch P. Interactions between Hb, Mg, DPG, ATP, and Cl determine the change in Hb‐O2‐affinity at high altitude. J Appl Physiol 74(1): 40‐48, 1993.
 144. Mairbäurl H, Schobersberger W, Hasibeder W, Knapp E, Hopferwieser T, Dittrich P. Increase in Hb‐O2‐affinity at moderate altitude (2000 m) in patients on maintenance hemodialysis. Clin Nephrol 31(4): 198‐203, 1989.
 145. Mairbäurl H, Schobersberger W, Hasibeder W, Schwaberger G, Gaesser G, Tanaka KR. Regulation of red cell 2,3‐DPG and Hb‐O2‐affinity during acute exercise. Eur J Appl Physiol 55: 174‐180, 1986.
 146. Mairbäurl H, Schobersberger W, Humpeler E, Hasibeder W, Fischer W, Raas E. Beneficial effects of exercising at moderate altitude on red cell oxygen transport and on exercise performance. Pflügers Arch Eur J Physiol 406: 594‐599, 1986.
 147. Mairbäurl H, Schobersberger W, Oelz O, Bärtsch P, Eckardt KU, Bauer C. Unchanged in‐vivo P50 at high altitude despite decreased red cell age and elevated 2,3‐DPG. J Appl Physiol 68(3): 1186‐1194, 1990.
 148. McMahon TJ, Moon RE, Luschinger BP, Carraway MS, Stone AE, Stolp BW, Gow AJ, Pawloski JR, Watke P, Singel DJ, Piantadosi CA, Stamler JS. Nitric oxide in the human respiratory cycle. Nat Med 8: 711‐717, 2002.
 149. Monod J, Wyman J, Changeux JP. On the nature of allosteric transitions: A plausible model. J Mol Biol 12: 88‐118, 1965.
 150. Mylvaganam SE, Bonaventura C, Bonaventura J, Getzoff ED. Structural basis for the Root effect in haemoglobin. Nat Struct Biol 3: 275‐283, 1996.
 151. Nielsen MS, Weber RE. Antagonistic interaction between oxygenation‐linked lactate and CO2 binding to human hemoglobin. Comp Biochem Physiol A Mol Integr Physiol 146: 429‐434, 2007.
 152. Nigen AM, Manning JM, Alben JO. Oxygen‐linked binding sites for inorganic anions to hemoglobin. J Biol Chem 255: 5525‐5529, 1980.
 153. Nikinmaa M. Membrane transport and control of hemoglobin‐oxygen affinity in nucleated erythrocytes. Physiol Rev 72: 301‐321, 1992.
 154. O'Donnell S, Mandaro R, Schuster TM, Arnone A. X‐ray diffraction and solution studies of specifically carbamylated human hemoglobin A. Evidence for the location of a proton‐ and oxygen‐linked chloride binding site at valine 1 alpha. J Biol Chem 254: 12204‐12208, 1979.
 155. Okada Y, Tyuma I, Sugimoto T. Evaluation of Severinghaus’ equation and its modification for 2, 3‐DPG. Jap J Physiol 27: 135‐144, 1977.
 156. Okada Y, Tyuma I, Ueda Y, Sugimoto T. Effect of carbon monoxide on equilibrium between oxygen and hemoglobin. Am J Physiol 230: 471‐475, 1976.
 157. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium‐derived relaxing factor. Nature 327: 524‐526, 1987.
 158. Passow H. Anion transport across the red blood cell membrane and the protein in band 3. Acta Biol Med Ger 36: 817‐821, 1977.
 159. Pelster B, Weber RE. Influence of organic phosphates on the Root effect of multiple fish haemoglobins. J Exp Biol 149: 425‐437, 1990.
 160. Pelster B, Weber RE. The physiology of the Root effect. Adv Comp Environm Physiol 8: 51‐77, 1991.
 161. Perrella M, Kilmartin JV, Fogg J, Rossi‐Bernardi L. Identification of the high and low affinity CO2‐binding sites of human haemoglobin. Nature 256: 759‐761, 1975.
 162. Perry SF, Daxboeck C, Emmett B, Hochachka PW, Brill RW. Effects of temperature change on acid‐base regulation in skipjack tuna (Katsuwonus pelamis) blood. Comp Biochem Physiol A Comp Physiol 81: 49‐53, 1985.
 163. Perutz MF. Stereochemistry of cooperative effects in haemoglobin. Nature 228: 726‐739, 1970.
 164. Perutz MF. Regulation of oxygen affinity of hemoglobin: Influence of structure of the globin on the heme iron. Annu Rev Biochem 48: 327‐386, 1979.
 165. Perutz MF. Species adaptation in a protein molecule. Mol Biol Evol 1: 1‐28, 1983.
 166. Perutz MF, Muirhead H, Mazzarella L, Crowther RA, Greer J, Kilmartin JV. Identification of residues responsible for the alkaline Bohr effect in haemoglobin. Nature 222: 1240‐1243, 1969.
 167. Pesce A, Bolognesi M, Bocedi A, Ascenzi P, Dewilde S, Moens L, Hankeln T, Burmester T. Neuroglobin and cytoglobin. Fresh blood for the vertebrate globin family. Embo Rep 3: 1146‐1151, 2002.
 168. Petschow D, Würdinger I, Baumann R, Duhm J, Braunitzer G, Bauer C. Causes of high blood O2 affinity of animals living at high altitude. J Appl Physiol 42: 139‐143, 1977.
 169. Petschow R, Petschow D, Bartels R, Baumann R, Bartels H. Regulation of oxygen affinity in blood of fetal, newborn and adult mouse. Respir Physiol 35: 271‐282, 1978.
 170. Pettigrew DW, Romeo PH, Tsapis A, Thillet J, Smith ML, Turner BW, Ackers GK. Probing the energetics of proteins through structural perturbation: Sites of regulatory energy in human hemoglobin. Proc Natl Acad Sci U S A 79: 1849‐1853, 1982.
 171. Piccinini M, Kleinschmidt T, Jurgens KD, Braunitzer G. Primary structure and oxygen‐binding properties of the hemoglobin from guanaco (Lama guanacoe, Tylopoda). Biol Chem Hoppe Seyler 371: 641‐648, 1990.
 172. Poyart C, Wajcman H, Kister J. Molecular adaptation of hemoglobin function in mammals. Respir Physiol 90: 3‐17, 1992.
 173. Pugh LG, Gill MB, Lahiri S, Milledge JS, Ward MP, West JB. Muscular exercise at great altitudes. J Appl Physiol 19: 431‐440, 1964.
 174. Rapoport S. The regulation of glycolysis in mammalian erythrocytes. Essays Biochem 4: 69‐103, 1968.
 175. Rapoport S, Guest GM. Distribution of acid soluble phosphorus in the blood of various vertebrates. J Biol Chem 131: 269‐282, 1941.
 176. Razynska A, Fronticelli C, Di Cera E, Gryczynski Z, Bucci E. Effect of temperature on oxygen affinity and anion binding of bovine hemoglobin. Biophys Chem 38: 111‐115, 1990.
 177. Reed PW. Effects of the divalent cation ionophore A23187 on potassium permeability of rat erythrocytes. J Biol Chem 251: 3489‐3494, 1976.
 178. Reeves RB. Temperature and acid‐base balance effects on oxygen transport by human blood. Respir Physiol 33: 99‐102, 1978.
 179. Reeves RB. A rapid micro method for obtaining oxygen equilibrium curves on whole blood. Respir Physiol 42: 299‐315, 1980.
 180. Reeves RB. The role of blood oxygen affinity in oxygen delivery to cold tissues. In: Sutton JR, Houston CS, Coates G, editors. Hypoxia and Cold. New York: Praeger, 1987, p. 89‐99.
 181. Richard V, Dodson GG, Mauguen Y. Human deoxyhaemoglobin‐2,3‐diphosphoglycerate complex low‐salt structure at 2·5 Å resolution. J Mol Biol 233: 270‐274, 1993.
 182. Riggs AF, Gorr TA. A globin in every cell? Proc Natl Acad Sci U S A 103: 2469‐2470, 2006.
 183. Rollema HS, Bauer C. The interaction of inositol pentaphosphate with the hemoglobins of highland and lowland geese. J Biol Chem 254: 12038‐12043, 1979.
 184. Rollema HS, de Bruin SH, Janssen LHM, van Os GAJ. The effect of potassium chloride on the Bohr effect of human hemoglobin. J Biol Chem 250/4: 1333‐1339, 1975.
 185. 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. J Physiol 189: 1‐29, 1967.
 186. Roughton FJ. Thermochemistry of the oxygen‐haemoglobin reaction: Direct measurements of the heat of reaction under various conditions. Biochem J 29: 2604‐2621, 1935.
 187. Roughton FJ, Adair GS, Barcroft J, Goldschmidt G, Herkel W, Hill RM, Keys AB, Ray GB. The thermochemistry of the oxygen‐haemoglobin reaction: Comparison of the heat as measured directly on purified haemoglobin with that calculated indirectly by the Van't Hoff Isochore. Biochem J 30: 2117‐2133, 1936.
 188. Roughton FJ, Otis AB, Lyster RL. The determination of the individual equilibrium constants of the four intermediate reactions between oxygen and sheep haemoglobin. Proc R Soc Lond B Biol Sci 144: 29‐54, 1955.
 189. Roughton FJ, Severinghaus JW. Accurate determination of O2 dissociation curve of human blood above 98.7 percent saturation with data on O2 solubility in unmodified human blood from 0 degrees to 37 degrees C. J Appl Physiol 35: 861‐869, 1973.
 190. Rumi E, Passamonti F, Pagano L, Ammirabile M, Arcaini L, Elena C, Flagiello A, Tedesco R, Vercellati C, Marcello AP, Pietra D, Moratti R, Cazzola M, Lazzarino M. Blood p50 evaluation enhances diagnostic definition of isolated erythrocytosis. J Intern Med 265: 266‐274, 2009.
 191. Salak J, VodrazkA Z. Acetylation of human haemoglobin and globin. I. Reactivity and accessibility of the functional groups. Biochim Biophys Acta 65: 115‐120, 1962.
 192. Samaja M. Hypoxia‐dependent protein expression: Erythropoietin. High Alt Med Biol 2: 155‐163, 2001.
 193. Samaja M, Brenna L, Allibardi S, Cerretelli P. Human red blood cell aging at 5,050‐m altitude: A role during adaptation to hypoxia. J Appl Physiol 75: 1696‐1701, 1993.
 194. Samaja M, Crespi T, Guazzi M, Vandegriff KD. Oxygen transport in blood at high altitude: Role of the hemoglobin‐oxygen affinity and impact of the phenomena related to hemoglobin allosterism and red cell function. Eur J Appl Physiol 90: 351‐359, 2003.
 195. Samaja M, DiPrampero PE, Cerretelli P. Simulation of oxygen delivery to tissues: The role of the hemoglobin oxygen equilibrium curve at altitude. Int J Clin Monit Comp 2: 95‐99, 1985.
 196. Samaja M, Mariani C, Prestini A, Cerretelli P. Acid‐base balance and O2 transport at high altitude. Acta Physiol Scand 159: 249‐256, 1997.
 197. Samaja M, Melotti D, Rovida E, Rossi‐Bernardi L. Effect of temperature on the p50 value for human blood. Clin Chem 29: 110‐114, 1983.
 198. Samaja M, Mosca A, Luzzana M, Rossi‐Bernardi L, Winslow RM. Equations and nomogram for the relationship of human blood p50 to 2,3‐diphosphoglycerate, CO2, and H+. Clin Chem 27(11): 1856‐1861, 1981.
 199. Samaja M, Rovida E. A new method to measure the hemoglobin oxygen saturation by the oxygen electrode. J Biochem Biophys Meth 7: 143‐152, 1983.
 200. Samaja M, Veicsteinas A, Cerretelli P. Oxygen affinity of blood in altitude sherpas. J Appl Physiol 47: 337‐341, 1979.
 201. Samaja M, Winslow RM. The separate effects of H+ and 2,3‐DPG on the oxygen equilibrium curve of human blood. Br J Haematol 41: 373‐381, 1979.
 202. Schechter AN. Hemoglobin research and the origins of molecular medicine. Blood 112: 3927‐3938, 2008.
 203. Schmidt W, Prommer N. Impact of alterations in total hemoglobin mass on VO2max. Exerc Sport Sci Rev 38: 68‐75, 2010.
 204. Schmidt‐Nielsen K, Larimer JL. Oxygen dissociation curves of mammalian blood in relation to body size. Am J Physiol 195: 424‐428, 1958.
 205. Severinghaus JW. Oxyhemoglobin dissociation curve correction for temperature and pH variation in human blood. J Appl Physiol 12: 485‐486, 1958.
 206. Severinghaus JW. Simple, accurate equations for human blood O2 dissociation computations. J Appl Physiol 46(3): 599‐602, 1979.
 207. Sick H, Gersonde K. Method for continuous registration of O2‐binding curves of hemoproteins by means of a diffusion chamber. Analyt Biochem 32: 362‐376, 1969.
 208. Siri WE, Van Dyke DC, Winchell HS, Pollycove M, Parker HG, Cleveland AS. Early erythropoietin, blood, and physiological responses to severe hypoxia in man. J Appl Physiol 21: 73‐80, 1966.
 209. Smith RC, Garbutt GJ, Isaacks RE, Harkness DR. Oxygen binding of fetal and adult bovine hemoglobin in the presence of organic phosphates and uric acid riboside. Hemoglobin 3: 47‐55, 1979.
 210. Snyder LR. Low P50 in deer mice native to high altitude. J Appl Physiol 58: 193‐199, 1985.
 211. Snyder LR, Born S, Lechner AJ. Blood oxygen affinity in high‐ and low‐altitude populations of the deer mouse. Respir Physiol 48: 89‐105, 1982.
 212. Stamatoyannopoulos G, Parer JT, Finch CA. Physiologic implications of a hemoglobin with decreased oxygen affinity (hemoglobin seattle). N Engl J Med 281: 916‐919, 1969.
 213. Stamler JS, Jia L, Eu JP, McMahon TJ, Demchenko IT, Bonaventura J, Gernert K, Piantadosi CA. Blood flow regulation by S‐nitrosohemoglobin in the physiological oxygen gradient. Science 276: 2034‐2037, 1997.
 214. Stephens AD. Polycythaemia and high affinity haemoglobins. Br J Haematol 36: 153‐159, 1977.
 215. Storz JF. Hemoglobin function and physiological adaptation in high‐altitude mammals. J Mammalogy 88: 24‐31, 2007.
 216. Storz JF, Moriyama H. Mechanisms of hemoglobin adaptation to high altitude hypoxia. High Alt Med Biol 9: 148‐157, 2008.
 217. Storz JF, Sabatino SJ, Hoffmann FG, Gering EJ, Moriyama H, Ferrand N, Monteiro B, Nachman MW. The molecular basis of high‐altitude adaptation in deer mice. PLoS Genet 3: e45, 2007.
 218. Sun XG, Hansen JE, Ting H, Chuang ML, Stringer WW, Adame D, Wasserman K. Comparison of exercise cardiac output by the Fick principle using oxygen and carbon dioxide. Chest 118: 631‐640, 2000.
 219. Sutherland‐Smith AJ, Baker HM, Hofmann OM, Brittain T, Baker EN. Crystal structure of a human embryonic haemoglobin: The carbonmonoxy form of gower II (alpha2 epsilon2) haemoglobin at 2.9 A resolution. J Mol Biol 280: 475‐484, 1998.
 220. Sutton JR, Reeves JT, Wagner PD, GROVES BM, Cymerman A, Malconian MK, Rock PB, Young PM, Walter SD, Houston CS. Operation Everest II: Oxygen transport during exercise at extreme simulated altitude. J Appl Physiol 64: 1309‐1321, 1988.
 221. Syllm‐Rapoport I, Jacobasch G, Roigas H, Rapoport S. [2,3‐PGase deficiency as a possible cause of increased ATP‐content]. Folia Haematol Int Mag Klin Morphol Blutforsch 83: 363‐365, 1965.
 222. Szabo A, Karplus M. Analysis of the interaction of organic phosphates with hemoglobin. Biochem 15: 2869‐2877, 1976.
 223. Tanaka KR, Paglia DE. Pyruvate kinase deficiency. Semin Hematol 8: 367‐396, 1971.
 224. Tenney SM. Functional significance of differences in mammalian hemoglobin affinity for oxygen. In: Sutton JR, Houston CS, Coates G, editors. Hypoxia and the Brain. Burlington: Queen City Printers, 1995, p. 57‐68.
 225. Tomita S. Modulation of the oxygen equilibria of human fetal and adult hemoglobins by 2,3‐diphosphoglyceric acid. J Biol Chem 256: 9495‐9500, 1981.
 226. Torelli G, Celentano F, Cortili G, D'Angelo E, Cazzaniga A, Radford EP. Hemoglobin‐oxygen equilibrium at different hemoglobin and 2,3‐diphosphoglycerate concentrations. Physiol Chem Physics 9/1: 21‐38, 1977.
 227. Tornqvist M, Osterman‐Golkar S, Kautiainen A, Naslund M, Calleman CJ, Ehrenberg L. Methylations in human hemoglobin. Mutat Res 204: 521‐529, 1988.
 228. Torrance J, Jacobs P, Restrepo A, Eschbach J, Lenfant C, Finch CA. Intraerythrocytic adaptation to anemia. N Engl J Med 283: 165‐169, 1970.
 229. Tuchinda S, Nagai K, Lehmann H. Oxygen dissociation curve of haemoglobin Portland. FEBS Lett 49(3): 390‐391, 1975.
 230. Tucker VA. Method for oxygen content and dissociation curves on microliter blood samples. J Appl Physiol 23: 410‐414, 1967.
 231. Turek Z, Kreuzer F, Hoofd LJC. Advantage or disadvantage of a decrease of blood oxygen affinity for tissue oxygen supply at hypoxia. Pflügers Arch Eur J Physiol 342: 185‐197, 1973.
 232. Tyuma I, Shimizu K, Imai K. Effect of 2,3‐Diphosphoglycerate on the cooperativity in oxygen binding of human adult hemoglobin. Biochem Biophys Res Commun 43: 423‐428, 1971.
 233. Val AL. Organic phosphates in the red blood cells of fish. Comp Biochem Physiol A Mol Integr Physiol 125: 417‐435, 2000.
 234. Valentine WN, Tanaka KR, Paglia DE. Hemolytic anemias and erythrocyte enzymopathies. Ann Intern Med 103: 245‐257, 1985.
 235. Valeri CR, Fortier NL. Red‐cell 2,3‐diphosphoglycerate and creatine levels in patients with red‐cell mass deficits or with cardiopulmonary insufficiency. N Engl J Med 281: 1452‐1455, 1969.
 236. van Beek GG, Zuiderweg ER, de Bruin SH. The binding of chloride ions to ligated and unligated human hemoglobin and its influence on the Bohr effect. Eur J Biochem 99: 379‐383, 1979.
 237. Van Beek GGM, de Bruin SH. The pH dependence of the binding of d‐glycerate 2,3‐bisphosphate to doexyhemoglobin and oxyhemoglobin. Eur J Biochem 100: 497‐502, 1979.
 238. Vane JR, Mitchell JA, Appleton I, Tomlinson A, Bishop‐Bailey D, Croxtall J, Willoughby DA. Inducible isoforms of cyclooxygenase and nitric‐oxide synthase in inflammation. Proc Natl Acad Sci U S A 91: 2046‐2050, 1994.
 239. Vora S, Davidson M, Seaman C, Miranda AF, Noble NA, Tanaka KR, Frenkel EP, DiMauro S. Heterogeneity of the molecular lesions in inherited phosphofructokinase deficiency. J Clin Invest 72: 1995‐2006, 1983.
 240. Wajcman H, Galacteros F. Hemoglobins with high oxygen affinity leading to erythrocytosis. New variants and new concepts. Hemoglobin 29: 91‐106, 2005.
 241. Walder JA, Chatterjee R, Steck TL, Low PS, Musso GF, Kaiser ET, Rogers PH, Arnone A. The interaction of hemoglobin with the cytoplasmic domain of band 3 of the human erythrocyte membrane. J Biol Chem 259: 10238‐10246, 1984.
 242. Weatherall DJ, Clegg JB, Wood WG, Pasvol G. Human haemoglobin genetics. Ciba Found Symp 147‐186, 1979.
 243. Weber RE. Cationic control of O2 affinity in lugworm erythrocruorin. Nature 292: 386‐387, 1981.
 244. Weber RE. Functional significance and structural basis of multiple hemoglobins with special reference to ectothermic vertebrates. In: Truchot J‐P, Lahlou B, editors. Animal Nutrition and Transport Processes. 2. Transport, Respiration and Excretion: Comparative and Environmental Aspects. Basel: Karger, 1990, p. 58‐75.
 245. Weber RE. Hemoglobin‐based O2 transfer in viviparous animals. Isr J Zool 40: 541‐550, 1994.
 246. Weber RE. Hemoglobin adaptations to hypoxia and altitude ‐ the phylogenetic perspective. In: Sutton JR, Houston CS, Coates G, editors. Hypoxia and the Brain. Burlington: Queen City Printers, 1995, p. 31‐44.
 247. Weber RE. Adaptations for oxygen transport: Lessons from fish hemoglobins. In: DiPrisco G, Giardina B, Weber RE, editors. Hemoglobin Function in Vertebrates. Molecular Adaptation in Extreme and Temperate Environments. Milano: Springer, 2000, p. 23‐37.
 248. Weber RE. High‐altitude adaptations in vertebrate hemoglobins. Respir Physiol Neurobiol 158: 132‐142, 2007.
 249. Weber RE, Campbell KL. Temperature dependence of haemoglobin‐oxygen affinity in heterothermic vertebrates: Mechanisms and biological significance. Acta Physiologica 202: 549‐562, 2011.
 250. Weber RE, Campbell KL, Fago A, Malte H, Jensen FB. ATP‐induced temperature independence of hemoglobin‐O2 affinity in heterothermic billfish. J Exp Biol 213: 1579‐1585, 2010.
 251. Weber RE, deWilde JAM. Multiple haemoglobins in plaice and flounder and their functional properties. Comp Biochem Physiol 54B: 433‐437, 1976.
 252. Weber RE, Fago A. Functional adaptation and its molecular basis in vertebrate hemoglobins, neuroglobins and cytoglobins. Respir Physiol Neurobiol 144: 141‐159, 2004.
 253. Weber RE, Hiebl I, Braunitzer G. High altitude and hemoglobin function in the vultures Gyps rueppellii and Aegypius monachus. Biol Chem Hoppe Seyler 369: 233‐240, 1988.
 254. Weber RE, Jensen FB, Cox RP. Analysis of teleost hemoglobin by Adair and Monod‐Wyman‐Changeux models. Effects of nucleoside triphosphates and pH on oxygenation of tench hemoglobin. J Comp Physiol 157B: 145‐152, 1987.
 255. Weber RE, Jessen TH, Malte H, Tame J. Mutant hemoglobins (alpha 119‐Ala and beta 55‐Ser): Functions related to high‐altitude respiration in geese. J Appl Physiol 75: 2646‐2655, 1993.
 256. Weber RE, Kleinschmidt T, Braunitzer G. Embryonic pig hemoglobins Gower I (zeta 2 epsilon 2), Gower II (alpha 2 epsilon 2), Heide I (zeta 2 theta 2) and Heide II (alpha 2 theta 2): Oxygen‐binding functions related to structure and embryonic oxygen supply. Respir Physiol 69: 347‐357, 1987.
 257. Weber RE, Lykkeboe G. Respiratory adaptations in carp blood. Influences of hypoxia, red cell organic phosphates, divalent cations and CO2 on hemoglobin‐oxygen affinity. J Comp Physiol 128: 127‐137, 1978.
 258. Weber RE, Vinogradov SN. Nonvertebrate hemoglobins: Functions and molecular adaptations. Physiol Rev 81: 569‐628, 2001.
 259. Weber RE, Voelter W. ‘Novel’ factors that regulate oxygen binding in vertebrate hemoglobins. Micron 35: 45‐46, 2004.
 260. Weber RE, Wood SC, Lomholt JP. Temperature acclimation and oxygen‐binding properties of blood and multiple haemoglobins of rainbow trout. J Exp Biol 65: 333‐345, 1976.
 261. Wells RMG. Haemoglobin‐oxygen affinity in developing embryonic erythroid cells of the mouse. J Comp Physiol 129: 333‐338, 1979.
 262. Wells RMG, Weber RE. The measurement of oxygen affinity in blood and haemoglobin solutions. In: Bridges CR, Butler PJ, editors. Techniques in Comparative Respiratory Physiology: An Experimental Approach, Society for Experimental Biology Seminar Series. Cambridge: Cambridge University Press, 1989, p. 279‐303.
 263. Wild BJ, Bain BJ. Detection and quantitation of normal and variant haemoglobins: An analytical review. Ann Clin Biochem 41: 355‐369, 2004.
 264. Willford DC, Hill EP, Moores WY. Theoretical analysis of optimal P50. J Appl Physiol 52: 1043‐1048, 1982.
 265. Winslow RM, Monge C. Hypoxia, Polycythemia, and Chronic Mountain Sickness. Baltimore: Johns Hopkins University Press, 1987.
 266. Winslow RM, Monge CC, Brown EG, Klein HG, Sarnquist F, Winslow NJ, McKneally SS. Effects of hemodilution on O2 transport in high altitude polycythemia. J Appl Physiol 59: 1495‐1502, 1985.
 267. Winslow RM, Monge CC, Statham NJ, Gibson CG, Charache S, Whittembury J, Moran O, Berger RL. Variability of oxygen affinity of blood: Human subjects native to high altitude. J Appl Physiol 51(6): 1411‐1416, 1981.
 268. Winslow RM, Samaja M, West JB. Red cell function at extreme altitude on Mount Everest. J Appl Physiol 56(1): 109‐116, 1984.
 269. Winslow RM, Samaja M, Winslow NJ, Rossi‐Bernardi L, Shrager RI. Simulation of continuous blood O2 equilibrium curve over physiological pH, DPG, and PCO2 range. J Appl Physiol 529: 524‐529, 1983.
 270. Winslow RM, Swenberg ML, Berger RL, Shrager RI, Luzzana M, Samaja M, Rossi‐Bernardi L. Oxygen equilibrium curve of normal human blood and its evaluation by Adair's equation. J Biol Chem 252/7: 2331‐2337, 1977.
 271. Wood SC, Johansen K. Blood oxygen transport and acid‐base balance in eels during hypoxia. Am J Physiol 225: 849‐851, 1973.
 272. Wood WG. Haemoglobin synthesis during human fetal development. Br Med Bull 32: 282‐287, 1976.
 273. Wood WG, Weatherall DJ. Haemoglobin synthesis during human foetal development. Nature 244: 162‐165, 1973.
 274. Woodson RD. Evidence that changes in blood oxygen affinity modulate oxygen delivery: Implications for control of tissue PO2 gradients. Adv Exp Med Biol 222: 309‐313, 1988.
 275. Wyman J, Jr. Heme proteins. Adv Protein Chem 4: 407‐531, 1948.
 276. Wyman J, Jr. Linked functions and reciprocal effects in hemoglobin: A second look. Adv Protein Chem 19: 223‐286, 1964.
 277. Yokoyama T, Chong KT, Miyazaki G, Morimoto H, Shih DT, Unzai S, Tame JR, Park SY. Novel mechanisms of pH sensitivity in tuna hemoglobin: A structural explanation of the Root effect. J Biol Chem 279: 28632‐28640, 2004.
 278. Yonetani T, Tsuneshige A, Zhou Y, Chen X. Electron paramagnetic resonance and oxygen binding studies of alpha‐Nitrosyl hemoglobin. A novel oxygen carrier having no‐assisted allosteric functions. J Biol Chem 273: 20323‐20333, 1998.
 279. Zheng T, Zhu Q, Brittain T. Origin of the suppression of chloride ion sensitivity in human embryonic hemoglobin Gower II. Iubmb Life 48: 435‐437, 1999.
 280. Zhou ZQ, Chen LC, Chen PF, Zhang KQ, Wang YH. Hemoglobin Hangzhou alpha 64(E13)Asp—‐Gly. A new variant found in China. Hemoglobin 11: 31‐33, 1987.
 281. Zwart A, Kwant G, Oeseburg B, Zijlstra WG. Human whole‐blood oxygen affinity: Effect of carbon monoxide. J Appl Physiol 57: 14‐20, 1984.

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Article Title: Oxygen Transport by Hemoglobin
 

How to Cite

Heimo Mairbäurl, Roy E. Weber. Oxygen Transport by Hemoglobin. Compr Physiol 2012, 2: 1463-1489. doi: 10.1002/cphy.c080113