Anionic control of hemoglobin function

TLDR: It appears that in normal human hemoglobin the binding of anionic cofactors directly influences the oxygen affinity by neutralizing the charged groups of the diphosphoglycerate binding site and thereby stabilizing the deoxy conformation.

Abstract: Hemoglobin is in a state of dynamic equilibrium between high and low affinity forms As in the case of many other enzymes, the equilibrium can be shifted by binding effector molecules at sites remote from the protein's active site We do not yet know the rules by which nature has chosen anionic or cationic effectors as control molecules for specific enzyme forms, but it appears clear that in the case of human hemoglobin the oxygen affinity is primarily modulated by the concentration of anions in the external medium In many laboratories around the world the question of how this anionic control is achieved is under investigation This investigation began many years ago and many of the questions that faced early investigators of hemoglobin function are still facing researchers today Detailed studies of the structural and functional properties of human hemoglobin variants have provided greater insight into the mechanism by which cofactor binding is linked to oxygen binding Of particular interest in this regard are the substitutions which involve the eight positively charged residues of the 2,3-diphosphoglycerate binding site The characteristics of these hemoglobin mutants and their response to organic and inorganic anions suggest that the equilibrium between high and low affinity conformations of hemoglobin is strongly affected by the net positive charge in the central cavity Thus it appears that in normal human hemoglobin the binding of anionic cofactors directly influences the oxygen affinity by neutralizing the charged groups of the diphosphoglycerate binding site and thereby stabilizing the deoxy conformation