Hemoglobin allosteric effectors

FIGURE 15.36 The structure, in ionic form, of BPG or 2,3-bisphosphoglycerate, an important allosteric effector for hemoglobin. 

Since this structure was first proposed, Braunitzer and co-workers have determined the amino acid sequence of rhinoceros hemoglobin (23a). Its allosteric effector site shows only a single substitution compared to that of human hemoglobin—His NA2/8 — Glu—yet ATP lowers its oxygen affinity more than DPG, and GTP lowers it more than ATP, just as in teleost fish (R. Baumann, unpublished observations). This observation supports the hydrogen bond between N-6 of the adenine and Glu NA2 proposed in Fig. 6 in fact it can hardly be explained without that bond. 

Case Study The Discovery and Development of Allosteric Effectors of Hemoglobin... 

The interactions between the allosteric effectors and hemoglobin add hydrogen bonds to the Hb tense state, similar to DPG, and therefore stabilize that state, resulting in an increased delivery of oxygen. 

On the other hand, small start-up companies focused intensely and entirely on what they were created to do, with the incentive that early and even later employees would be well rewarded if the venture was successful. It was clear to me, in this case, that if the translation from basic and preclinical research to clinical trials were to occur, our best chance was to initiate a company. For the most part, big pharmaceutical houses have stayed clear of allosteric effectors as drugs. We had the enormous advantage that far more is known about hemoglobin as an allosteric protein than any other. 

Saeo, M.K., Moure, C.M., Burnett, J.C., Joshi, G.S., and Abraham, D.J. High-resolution crystal structure of deoxy hemoglobin complexed with a potent allosteric effector. Protein Sci. 2001, 10, 951-957. 

Various allosteric effectors influence the equilibrium between the T and R forms and thereby regulate the O2 binding behavior of hemoglobin (yellow arrows). The most important effectors are CO2, and 2,3-bisphospho-glycerate (see p. 282). 

When erythrocytes circulate in underoxygenated tissue, release of 2,3-dipho-sphoglycerate (2,3-DPG) is increased. This release of 2,3-DPG lowers the affinity of hemoglobin for oxygen (2,3-DPG is an allosteric effector of hemoglobin). As a consequence, extraction of oxygen from blood by tissues is increased. Thus, PGK inhibition is a possible approach for treating cardiac and respiratory disorders. 

The structure of glycerate-2,3-bisphosphate, an allosteric effector for hemoglobin oxygen release. 

Glycerate-2,3-bisphosphate was encountered as an allosteric effector of hemoglobin. 

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