How Do Small Molecules Do Great Things?

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Abstract
In 1925 Greenwald discovered considerable quantities of 2,3-diphosphoglycerate (DPG) in mammalian red cells.1 The function of this small phosphate molecule in the erythrocyte remained a mystery, however, until we demonstrated over 40 years later that it is a powerful regulator of the oxygen affinity of hemoglobin.2 It was further shown that it acts by complexing hemoglobin in the deoxygenated state, a reaction that inhibits oxygen binding but facilitates its unloading at physiologic oxygen tensions.3 DPG thus functions as an essential cofactor of the oxygen carrier. Since the affinity of hemoglobin for oxygen and the organic phosphate is reciprocal, this mechanism . . .