Haemoglobin: The structural changes related to ligand binding and its allosteric mechanism

Quaternary structures and low frequency molecular vibrations of haems of deoxy and oxyhaemoglobin studied by resonance Raman scattering

Evidence from a number of vertebrate taxa suggests that modifications of hemoglobin (Hb) function may often play a key role in mediating an adaptive response to high altitude hypoxia. The respiratory functions of Hb are a product of the protein's intrinsic O(2)-binding affinity and its interactions with allosteric effectors such as protons, chloride ions, CO(2), and organic phosphates. Here we review several case studies involving high altitude vertebrates where it has been possible to identify specific mechanisms of Hb adaptation to hypoxia. In addition to comparative studies of Hbs from diverse animal species, functional studies of human Hb mutants also suggest that there is ample scope for evolutionary adjustments in Hb-O(2) affinity through alterations of the equilibrium constants of O(2) binding to deoxy- and oxyHb or through changes in the allosteric equilibrium constants for the transition between the deoxy- and oxyHb quaternary structures. It may be the case that certain evolutionary paths are followed more often than others simply because they are subject to less stringent pleiotropic constraints.

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Mechanisms of Hemoglobin Adaptation to High Altitude Hypoxia

Hemoglobin (Hb) constitutes a vital link between ambient O2 availability and aerobic metabolism by transporting oxygen (O2) from the respiratory surfaces of the lungs or gills to the O2-consuming tissues. The amount of O2 available to tissues depends on the blood-perfusion rate, as well as the arterio-venous difference in blood O2 contents, which is determined by the respective loading and unloading O2 tensions and Hb-O2-affinity. Short-term adjustments in tissue oxygen delivery in response to decreased O2 supply or increased O2 demand (under exercise, hypoxia at high altitude, cardiovascular disease, and ischemia) are mediated by metabolically induced changes in the red cell levels of allosteric effectors such as protons (H(+)), carbon dioxide (CO2), organic phosphates, and chloride (Cl(-)) that modulate Hb-O2 affinity. The long-term, genetically coded adaptations in oxygen transport encountered in animals that permanently are subjected to low environmental O2 tensions commonly result from changes in the molecular structure of Hb, notably amino acid exchanges that alter Hb's intrinsic O2 affinity or its sensitivity to allosteric effectors. Structure-function studies of animal Hbs and human Hb mutants illustrate the different strategies for adjusting Hb-O2 affinity and optimizing tissue oxygen supply.

Oxygen transport by hemoglobin.

Publisher Summary This chapter presents an overview of the measurement of binding of gaseous and nongaseous ligands to hemoglobins by conventional spectrophotometric procedures. Ferrous hemoproteins bind a number of gaseous and nongaseous ligands specifically at the heme group. The reactions are fully reversible and may be described, at equilibrium, by standard thermodynamic relationships involving the application of the law of mass action. Equilibrium studies of the interaction of hemoglobin with heme ligands have been simplified by spectrophotometric procedures relating the changes in absorption spectrum to the degree of saturation of hemoglobin with ligands. The main assumption on which the spectrophotometric methods are based is that, within a tetramer partially saturated with a ligand, the spectral properties of the free and of the bound hemes correspond to those of the fully unliganded protein and of the fully liganded protein, respectively. Thus, in the quantitative evaluation of the ligand binding isotherm, linearity of the relationships between combination with ligand and spectral changes is assumed. The chapter describes gaseous ligands and nongaseous ligands.

K. Imai

Papers

Role of Bohr group salt bridges in cooperativity in hemoglobin