Oxygen binding by sickle cell hemoglobin polymers

Sunshine, Helen R.; Hofrichter, James; Ferrone, Frank A.; Eaton, William A.

doi:10.1016/0022-2836(82)90432-6

Cited by 107 publications

(92 citation statements)

References 37 publications

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“…For this reason, it was important that we determine intracellular polymerization as a function of intracellular Hb concentration. In addition, recent progress in understanding the role of water nonideality in the polymerization process led to an improved thermodynamic formulation, which is in better agreement with the measured solubility of cell-free HbS solutions as a function of oxygen saturation (14)(15)(16).…”

Section: Introductionmentioning

confidence: 62%

“…Following the approach of our previous studies, to calculate the amount of polymer formed at varying oxygen saturations we used the thermodynamic theory for gelation developed by Minton (based on the twostate model for gelation and the nonideal behavior of Hb at physiologic concentrations) (4) as modified by Gill et al (15) to include the nonideal behavior of water. This is summarized by the equations of Sunshine et al (16). For i species of Hb in a gelled mixture, the activity coefficient y, of free hemoglobin in solution is related to the activity coefficient°' y of free Hb in a pure deoxyhemoglobin S gel by (1) where C, is the solubility of Hb in the mixture, C°is the solubility of pure deoxyhemoglobin S, xi is the solution mole fraction of species i, and ei is the relative tendency for species i to be incorporated into the polymer (e = 1 for pure deoxyhemoglobin S and e = 0 for HbF and the HbS/HbF hybrid (16,21) (y,,C,/y'yC) = 1/:xjej, (2) has been expanded by Gill et al (15) SS erythrocytes from four individuals with HbF levels varying from <2 to 6.3% were fractionated on Stractan gradients.…”

Section: Methodsmentioning

confidence: 99%

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Intracellular polymerization of sickle hemoglobin. Effects of cell heterogeneity.

Noguchi¹,

Torchia²,

Schechter³

1983

J. Clin. Invest.

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A B S T R A C T To determine the extent to which the broad distribution in intracellular hemoglobin concentrations found in sickle erythrocytes affects the extent of intracellular polymerization of hemoglobin S, we have fractionated these cells by density using discontinuous Stractan gradients. The amount of polymer formed in the subpopulations was experimentally measured as a function of oxygen saturation using '3C nuclear magnetic resonance spectroscopy. The results for each subpopulation are in very good agreement with the theoretical predictions based on the current thermodynamic description for hemoglobin S gelation. We further demonstrate that the erythrocyte density profile for a single individual with sickle cell anemia can be used with the theory to predict the amount of polymer in unfractionated cells. We find that heterogeneity in intracellular hemoglobin concentration causes the critical oxygen saturation for formation of polymer to shift from 84 to >90%; polymer is formed predominantly in the dense cells at the very high oxygen saturation values. The existence of polymer at arterial oxygen saturation values has significance for understanding the pathophysiology of sickle cell anemia.

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Section: Introductionmentioning

confidence: 62%

Section: Methodsmentioning

confidence: 99%

Intracellular polymerization of sickle hemoglobin. Effects of cell heterogeneity.

Noguchi¹,

Torchia²,

Schechter³

1983

J. Clin. Invest.

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“…However, the solubility of the deoxygenated form of HbS is ϳ17 g/dl at 37°C, whereas it is 70 g/dl for HbA (49). In vivo, HbS exceeds its solubility threshold when deoxygenated and polymerizes to form a gel (50), which is associated with a drastic decrease in its ligand-binding affinity (51)(52)(53)(54)(55)(56). Importantly, all heme concentrations used in studies summarized in Figs.…”

Section: Discussionmentioning

confidence: 99%

Nitrite Reductase Activity of Hemoglobin S (Sickle) Provides Insight into Contributions of Heme Redox Potential Versus Ligand Affinity

Grubina

Basu

Tiso

et al. 2008

Journal of Biological Chemistry

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Hemoglobin A (HbA) is an allosterically regulated nitrite reductase that reduces nitrite to NO under physiological hypoxia. The efficiency of this reaction is modulated by two intrinsic and opposing properties: availability of unliganded ferrous hemes and R-state character of the hemoglobin tetramer. Nitrite is reduced by deoxygenated ferrous hemes, such that heme deoxygenation increases the rate of NO generation. However, heme reactivity with nitrite, represented by its bimolecular rate constant, is greatest when the tetramer is in the R quaternary state. The mechanism underlying the higher reactivity of R-state hemes remains elusive. It can be due to the lower heme redox potential of R-state ferrous hemes or could reflect the high ligand affinity geometry of R-state tetramers that facilitates nitrite binding. We evaluated the nitrite reductase activity of unpolymerized sickle hemoglobin (HbS), whose oxygen affinity and cooperativity profile are equal to those of HbA, but whose heme iron has a lower redox potential. We now report that HbS exhibits allosteric nitrite reductase activity with competing proton and redox Bohr effects. In addition, we found that solution phase HbS reduces nitrite to NO significantly faster than HbA, supporting the thesis that heme electronics (i.e. redox potential) contributes to the high reactivity of R-state deoxy-hemes with nitrite. From a pathophysiological standpoint, under conditions where HbS polymers form, the rate of nitrite reduction is reduced compared with HbA and solution-phase HbS, indicating that HbS polymers reduce nitrite more slowly.The various redox reactions catalyzed by ferrous hemes of the heme-globins (primarily hemoglobin and myoglobin) have interested scientists for over 150 years (1). In 1901, while studying the mechanism of meat curing, John Haldane described the ability of nitrite to oxidize hemoglobin (Hb) 5 to methemoglobin (met-Hb) and generate iron-nitrosyl-hemoglobin (iron-nitrosyl-Hb) in sections of meat not exposed to air (2), although he was most likely observing the analogous reaction with myoglobin (Mb). The reaction of nitrite with deoxyhemoglobin (deoxy-Hb) was further characterized by Brooks in 1937 (3) and by Doyle and colleagues in 1981 (4). Recent work has demonstrated that deoxy-Hb can effectively catalyze the reduction of nitrite to NO along physiological oxygen and pH gradients (5-9). This reaction has been implicated in nitrite-and deoxy-Hb-dependent vasodilation in vivo (5, 10 -12) and in vitro (5, 13), as well as in nitrite-mediated cytoprotection following ischemia-reperfusion injury (14 -17). An analogous reaction of nitrite with deoxymyoglobin (deoxy-Mb) has been associated with the regulation of cardiomyocyte respiration during physiological and pathological hypoxia (18,19).In an anaerobic environment nitrite is reduced to NO as deoxy-Hb is oxidized to met-Hb (Equation 1) (6,20). NO generated in this reaction can then be bound by other ferrous deoxy-hemes to form iron-nitrosyl-Hb (Equation 2) (21).Importantly, this reaction is a...

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“…26 Hemoglobin F also inhibits hemoglobin S polymerization, 27 which would be expected to reverse in part the low oxygen affinity of hemoglobin S that results from its polymerization. 28 Therefore, hemoglobin F could conceivably contribute to a relative tissue hypoxia, despite its welldocumented effect in ameliorating the course of sickle cell disease and increasing patient survival. 29 In a sense, hemoglobin F's left shifting of the oxygen saturation curve is similar to what can be seen in sickle cell patients after red cell exchanges: both hemoglobin levels and blood oxygen affinity increase modestly after exchange and are associated with increased exercise capacity.…”

Section: Discussionmentioning

confidence: 99%

Relationship of erythropoietin, fetal hemoglobin, and hydroxyurea treatment to tricuspid regurgitation velocity in children with sickle cell disease

Gordeuk

Campbell

Rana

et al. 2009

Blood

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Hydroxyurea and higher hemoglobin F improve the clinical course and survival in sickle cell disease, but their roles in protecting from pulmonary hypertension are not clear. We studied 399 children and adolescents with sickle cell disease at steady state; 38% were being treated with hydroxyurea. Patients on hydroxyurea had higher hemoglobin concentration and lower values for a hemolytic component derived from 4 markers of hemolysis (P ≤ .002) but no difference in tricuspid regurgitation velocity compared with those not receiving hydroxyurea; they also had higher hemoglobin F (P < .001) and erythropoietin (P = .012) levels. Hemoglobin F correlated positively with erythropoietin even after adjustment for hemoglobin concentration (P < .001). Greater hemoglobin F and erythropoietin each independently predicted higher regurgitation velocity in addition to the hemolytic component (P ≤ .023). In conclusion, increase in hemoglobin F in sickle cell disease may be associated with relatively lower tissue oxygen delivery as reflected in higher erythropoietin concentration. Greater levels of erythropoietin or hemoglobin F were independently associated with higher tricuspid regurgitation velocity after adjustment for degree of hemolysis, suggesting an independent relationship of hypoxia with higher systolic pulmonary artery pressure. The hemolysis-lowering and hemoglobin F–augmenting effects of hydroxyurea may exert countervailing influences on pulmonary blood pressure in sickle cell disease.

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Oxygen binding by sickle cell hemoglobin polymers

Cited by 107 publications

References 37 publications

Intracellular polymerization of sickle hemoglobin. Effects of cell heterogeneity.

Intracellular polymerization of sickle hemoglobin. Effects of cell heterogeneity.

Nitrite Reductase Activity of Hemoglobin S (Sickle) Provides Insight into Contributions of Heme Redox Potential Versus Ligand Affinity

Relationship of erythropoietin, fetal hemoglobin, and hydroxyurea treatment to tricuspid regurgitation velocity in children with sickle cell disease

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