Molecular Pathology of Human Haemoglobin: Stereochemical Interpretation of Abnormal Oxygen Affinities

Allostery and cooperativity revisited

“…It has been argued, ''all proteins are allosteric'' (Gunasekaran et al 2004). This is analogous to the results for human hemoglobin, for which mutants with nearly every amino acid replaced individually are known, in part because they often cause diseases by their effect on oxygenation, and in part from the more general screening of hemoglobins of patients in hospitals (Morimoto et al 1971). The effect of many mutations has been difficult to interpret, in spite of the considerable available data, including X-ray structures of the mutants (Morimoto et al 1971;Fermi and Perutz 1981).…”

Hemoglobin E: Its oxygen affinity in relation with the ionic environment

“…The first oxygen equilibrium studies performed on blood or on intact cells, suggested an abnormally low oxygen affinity [ 21 and a tentative explanation was proposed at the molecular level [3]. In 1972, the oxygen equilibrium of hemoglobin E was more theroughly studied by Bunn et al [4] : they found an identical oxygen equilibrium in phosphate-free hemolysates of blood from E and A homozygotes and in purified components from heterozygotes.…”

Multiple strategies for O2 transport: from simplicity to complexity

“…The crucial role of several residues present in the heme distal pocket in determining the intrinsic reactivity toward ligands was elucidated for the different subunits (127), putting in evidence that the steric hindrance of the ValE11 residue and the polarity of the HisE7 residue are critical for a fine tuning of ligand binding to human Hb. However, most of these studies focused on the modulation of reactivity, which is easier to investigate, more than on the modulation of cooperativity and allosteric interactions, in particular at the a 1 b 2 interface, which is known to be the central region for the quaternary switch (128).…”