Regulation of oxygen affinity of mammalian haemoglobins

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Mammalian haemoglobins can be divided broadly into two groups: those with intrinsically high oxygen affinity, which is lowered by d-glycerate-2,3-bis (phosphate), and those with intrinsically low oxygen affinity and low sensitivity to DPG † † Abbreviations used: DPG, d-glycerate-2,3-bis (phosphate); Hb, haemoglobin; IHP, inositol hexaphosphate. . Human Hb is an example of the first and bovine Hb of the second group. We have measured the oxygen equilibrium curves of the two Hbs under various conditions and calculated their allosteric and Adair constants. In stripped solutions, bovine Hb has the same K R value as human, but a lower K T and a higher L value, showing that its low oxygen affinity arises from stronger constraints in the quaternary deoxy structure. However, the sequences of the low affinity Hbs show that their deoxy structures contain no additional salt bridges or hydrogen bonds either within or between the subunits. Amino acid replacements between species with intrinsically high or low oxygen affinity are mostly conservative and confined to external residues. The only common difference in amino acid sequence between the two groups is found in the residue in position NA2β, which is a hydrophilic residue in the first group and a large hydrophobic residue in the second group. The hydrophilic side-chain dips into the solvent, while the hydrophobic one must point into the interior of the β subunit. It is suggested that this side-chain locks helix A firmly to its neighbouring segments in the polypeptide chain, and by doing so, mimics the action of DPG in stabilizing the tertiary deoxy structure of the β subunits.