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Oxygen Transport by Hemoglobin

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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 . 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. .

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.

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 ].

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 ]. 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 . 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 ].

Figure 10. Figure 10.

Change in the expression of human globin genes during embryonic, fetal, and postnatal development [modified, with permission, After Wood and Schechter ]. 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 ].

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. using the formulas reported by Severinghaus . 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 . 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. .



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.



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 ].



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 ]. 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 . 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 ].



Figure 10.

Change in the expression of human globin genes during embryonic, fetal, and postnatal development [modified, with permission, After Wood and Schechter ]. 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 ].



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. using the formulas reported by Severinghaus . 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).

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