In the mutant hemoglobin Known as HB Providence, an asparagines residue in the -

Question

In the mutant hemoglobin Known as HB Providence, an asparagines residue in the -chain replaces Lys-82. In normal hemoglobin, Lys-82 projects into the central cavity of the hemoglobin molecule. Predict the effect of the Lys Asn mutation on the affinity of allosteric modifiers (relative to normal Hb e.g. HbA) and describe the effect the mutation would have on the function (oxygen binding) of HB providence. Under appropriate conditions, hemoglobin dissociates into its four subunits. Isolated a subunits bind oxygen, but the o_2 saturation curve is hyperbolic instead of sigmoidal. In addition, the saturation curve is not affected by the presence of H^+, CO_2, or BPG. What do these observations indicate about the cooperativity and allosterism observed in hemoglobin?

Explanation / Answer

Question 1:

An interesting article of Journal of Biological Chemistry addresses this issue:

Hemoglobin providence. Functional consequences of two alterations of the 2,3-diphosphoglycerate binding site at position beta 82. J Biol Chem. 1976 Dec 10;251(23):7563-71.

In short it states that in normal hemoglobin position beta 82 is normally occupied by lysine, a positively charged residue that is involved in the binding of anionic cofactors. In Hb Providence this residue is substituted by a neutral residue in Asn and by a negatively charged residue in Hb Providence Asp. Hb Providence resembles more normal HB than Hb Providence Asp. Nevertheless the replacement of a positive residue for a neutral one diminishes the affinity of the beta chain for charged cofactors, which in turns alters the normal function. Also, relative to Hb A, both Hb Providence Asn and Hb Providence Asp show decreased oxygen affinities at neutral pH in the absence of cofactors. The article explains very well these aspects.

Question 2:

Allosteric effect regulates deliver of oxygen to the tissues. Hemoglobin is a macromolecule that has multiple ligand binding sites. Allosteric effects can generate cooperative behavior which enhances the function. pH affects hemoglobin. At the capillary tissues pH is lower because there is low supply of oxygen, high levels of carbon dioxide which in water turns into carbonic acid. This lowering of pH enhances liberation of oxygen from hemoglobin so it gets delivered to the tissues.

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