Box An amino acid difference responsible for Hb S

A single amino acid substitution from glutamic acid to valine results in Hb S. Glutamic acid is negatively charged while valine is hydrophobic: the amino acid change in each of the P globin chains in the haemoglobin molecule promotes hydrophobic contacts with alanine, phenylalanine, and leucine residues in adjacent molecules such that there is reversible association in conditions of deoxygenation forming 14 stranded polymers which can crosslink, the long fibres stretching and deforming the red blood cells (Vekilov 2007).

Pauling published evidence of a difference in behaviour of haemoglobins from affected and unaffected individuals when subjected to gel electrophoresis (Pauling et al. 1949). The difference between unaffected and affected individuals was further refined by analysis of polypeptides resulting from enzymatic digestion of haemoglobin using electrophoresis and partition chromatography. This led to the discovery that a single amino acid, a change from glutamic acid to valine, was responsible for the difference between normal adult haemoglobin (Hb A) to haemoglobin S (Hb S, sickle variant haemoglobin) (see Fig. 1.1; Box 1.6) (Ingram 1957, 1958, 1959).

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