Abstract
A therapeutic agent capable of inhibiting the polymerization of hemoglobin S would relieve the symptoms of sickle cell disease. The P 50 of oxygen binding to hemoglobin A (HbA) in the presence of an effector has been used for the initial screening of potential antisickling agents. We evaluated the thermodynamic parameters, P 50, ΔG, ΔH, and ΔS and Hill coefficient for oxygen binding to human HbA o (HbA stripped of all endogenous effectors) in the presence of two antisickling agents, pyridoxal (PL) and pyridoxal 5′-phosphate (PLP), and two sickling-enhancing agents, 2,3-diphosphoglycerate (DPG) and inositol hexaphosphate (IHP). The P 50 of oxygen binding to HbA o in phosphate/EDTA buffer, pH 7.6, was found to be 560 Pa. The P 50 was increased to 653 Pa and 1746 Pa by DPG and IHP, respectively. The antisickling agents, PLP, and PL, had opposite effects on the P 50, shifting it to 840 Pa and 187 Pa, respectively, indicating that a decrease in P 50 may not be the best predictor of an antisickling agent. The Hill coefficient was 2.9 for both HbA o and HbA o + DPG and 2.6 for HbA o + IHP. The Hill coefficient was reduced by both PLP to 2.3 and by PL to 2.1. The enthalpies for oxygen binding to HbA o, HbA o + DPG, and HbA o + IHP were −48.1 kcal/mol Hb, −48.0 kcal/mol Hb, and −42.2 kcal/mol Hb, respectively. In contrast, the enthalpies for HbA o + PLP and HbA o + PL were −57.0 kcal/mol Hb and −51.1 kcal/mol Hb. Our study suggests that decreases in cooperativity and enthalpy, alone or in combination, may be useful indices of potential antisickling agents.
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