Deoxygenated sickle hemoglobin. Modulation of its solubility by 2,3-diphosphoglycerate and other allosteric polyanions

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The effects of 2,3-diphosphoglycerate (DPG) and other allosteric polyanions of the phosphate or sulfate ester class (inositol hexaphosphate (IHP), ATP, pyridoxamine-5'-phosphate (PMP), and inositol hexasulfate (IHS)) on the solubility of deoxyhemoglobin S, and the oxygen affinity of Hb A were evaluated. Their effects on the saturation concentration (c(sat)) indicated promotion of gelation in each case, according to the following order of molar effectiveness: IHP > IHS > DPG > ATP >> PMP. Four polybasic carboxylic acids (benzenetricarboxylate (trimesic acid), benzenetetracarboxylate (BTC), benzenepentacarboxylate (BPC), and benzenehexacarboxylate (BHC)) were evaluated as well. Their order of molar effectiveness was: BHC > BPC > BTC >> trimesic acid. Both classes of polyanions influenced oxygen affinity in the same order as solubility. Overall, a good correlation existed between the negative charges of these nine allosteric polyanions at neutral pH and their effects on solubility and oxygen affinity. Because of its possible role in the pathophysiology of sickle cell disease, the effect of DPG on c(sat) was examined over the pH range 6.5-7.6. While a decrease in c(sat) was observed for DPG-saturated deoxyhemoglobin S throughout this range, the decrement observed in the physiological pH range (1.8 g/dl) was somewhat lower than that below neutral pH (3.0 g/dl); in either case the sickling tendency of SS red cells would be enhanced. Inasmuch as the intracellular concentration of DPG in sickle cell anemia may be elevated as much as 2-fold, maneuvers aimed at its reduction could be therapeutically beneficial.

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