Biochemistry - Chemical Reactions in Living Cells, Volume 1 - D. Metzler 1980

How molecules join together
Cooperative conformational changes
Allosteric regulators

Conformational equilibria in Hemoglobin are influenced not only by the binding of oxygen to the heme groups, but also by the interaction of Other Compounds with various sites on the molecule. Such compounds are termed allosteric effectors or regulators, because they bind outside the Active Site to other Regions of the protein molecule. They are discussed in greater detail in Chapter 6 (Section B.6). An important allosteric effector for hemoglobin is 2,3-diphosphoglycerate, a compound present in unusually high concentrations in human erythrocytes (at approximately an equimolar ratio to hemoglobin).

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A single molecule of 2,3-diphosphoglycerate binds to one tetramer of deoxyhemoglobin with a dissociation constant of K = 1.4-10⁵. Its affinity for the oxy-form is approximately half as great [74]. X-ray crystallographic data indicate that 2,3-diphosphoglycerate binds between the two ß-chains of deoxyhemoglobin, right along the twofold axis of Symmetry (Fig. 4-19) [71]. It has long been known that hemoglobin in whole Blood has a lower oxygen affinity than isolated hemoglobin [75, 76] (Fig. 4-18). We now understand that this difference stems from the presence of 2,3-diphosphoglycerate within erythrocytes. This is a crucial physiological feature, as it enables red Blood Cells to deliver a larger fraction of their carried oxygen to the Tissues. The diphosphoglycerate content of erythrocytes varies depending on physiological conditions; for instance, its concentration is elevated in individuals living at high altitudes [76]. It has been suggested that artificially altering the concentration of this regulatory substance in red blood cells could have clinical Applications in treating Disorders of the Oxygen transport system. The presence of 2,3-diphosphoglycerate in red blood cells is not universal among species; in birds and turtles, it appears to be replaced by Inositol pentaphosphate.

Another example of Allosteric Regulation in hemoglobin was discussed in the previous section. The Bohr effect can be viewed as the action of protons serving as allosteric effectors that bind to the amino and imidazole groups involved in salt bridge formation. Carbon dioxide acts as another physiological effector, binding reversibly to the terminal NН₂ groups of the a- and ß-subunits to form carbamino (carbamate, —NH—СОО^-) groups [77, 78].

Deoxyhemoglobin exhibits a higher affinity for СО₂ than does the oxy-form. Consequently, the release of oxygen by oxyhemoglobin is facilitated in tissues rich in СО₂. Hemoglobin transports a significant portion of the СО₂ to the Lungs, where its oxygenation facilitates the dissociation of СО₂ from the carbamino groups.