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J Biol Chem, Vol. 274, Issue 36, 25550-25554, September 3, 1999

Additive Effects of  Chain Mutations in Low Oxygen Affinity Hemoglobin F41Y,K66T

From INSERM, Unité 473, 84 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre Cedex, France

In order to decrease significantly the oxygen affinity of human hemoglobin, we have associated the mutation F41Y with another point mutation also known to decrease the oxygen affinity of Hb. We have synthesized a recombinant Hb (rHb) with two mutations in the  chains: rHb F41Y,K66T. In the absence of 2,3-diphosphoglycerate, additive effects of the mutations are evident, since the doubly mutated Hb exhibits a larger decrease in oxygen affinity than for the individual single mutations. In the presence of 2,3-diphosphoglycerate, the second mutation did not significantly increase the P₅₀ value relative to the single mutations. However, the kinetics of CO binding still indicate combined effects on the allosteric equilibrium, as evidenced by more of the slow bimolecular phase characteristic of binding to the deoxy conformation.

Dimer-tetramer equilibrium studies indicate an increase in stability of the mutants relative to rHb A; the double mutant rHb F41Y,K66T at pH 7.5 showed a K_4,2 value of 0.26 µM. Despite the lower oxygen affinity, the single mutant F41Y and double mutant F41Y,K66T show only a moderate increase of 20% in the autoxidation rate. These mutations are thus of interest in developing a Hb-based blood substitute.

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