Structure-function relations of human hemoglobins

Abstract

In 1949 Pauling and his associates showed that sickle cell hemoglobin (HbS) belonged to an abnormal molecular species. In 1958 Ingram, who used a two-dimensional system of electrophoresis and chromatography to break down the hemoglobin molecule into a mixture of smaller peptides, defined the molecular defect in HbS by showing that it differed from normal adult hemoglobin by only a single peptide. Since then, more than 200 variant and abnormal hemoglobins have been described. Furthermore, the construction of an atomic model of the hemoglobin molecule based on a high-resolution x-ray analysis by Dr. Max Perutz at Cambridge has permitted the study of the stereochemical part played by the amino acid residues, which were replaced, deleted, or added to in each of the hemoglobin variants. Some of the variants have been associated with clinical conditions. The demonstration of a molecular basis for a disease was a significant turning point in medicine. A new engineered hemoglobin derived from crocodile blood, with markedly reduced oxygen affinity and increased oxygen delivery to the tissues, points the way for future advances in medicine.

Figure 1

Model of the hemoglobin molecule. Two identical white (alpha) polypeptide chains and two identical black (beta) polypeptide chains form a complete molecule. The hemes are shown as discs. O₂ marks the oxygen binding site. Reprinted courtesy of Dr. Max Perutz.

Figure 2

Diagrammatic representation of oxygen equilibrium curves of the lug worm, man, and hemoglobin Scuba. The effect of hydrogen ions, 2, 3-bisphosphoglycerate, and carbon dioxide (H⁺+BPG +CO₂) is to promote a right shift. If man had the hemoglobin of the lug worm (left shift), he would die of anoxia.

Figure 3

Diagrammatic representation of the heme pocket formed by amino acids. Oxygenation can occur only between the non-heme-linked histidine and iron.