The Interaction of Sickle Hemoglobin with DPG, CO₂ and with Other Hemoglobins: Formation of Asymmetrical Hybrids

Abstract

In either the red cell or in concentrated solution, deoxyhemoglobin S (α₂β₂ ^{6 val}) possesses the unique property of aggregating into microfilaments, leading to increased viscosity and ultimately to gelation. This property may be strongly influenced by the presence of non-S hemoglobins or by a second amino acid sub-stitution on either the β chain (hb C-Harlem (α₂β₂ ^{6 val 73 asn}) (Bookchin et. Al., 1967) or the α chain (hb Memphis (α₂ ^{23 gln β 6 val}) (Kraus et al., 1966). Furthermore, the sickling phenomenon may be affected by intracellular modifiers of hemoglobin function such as carbon dioxide (CO₂) and 2,3-diphosphoglycerate (DPG). Both of these co-factors bind to hemoglobin at N-terminal amino groups of globin polypeptide chains. Carbamino formation occurs at the N-terminal amino groups of both the α and the β chains (Kilmartin and Rossi-Bernardi, 1969) while DPG binds to positively charged sites on the β chains including the α amino group of NA1 valine, the imidazole of H21 histidine and the ɛ amino group of EF6 lysine (Perutz, 1970). It is of interest that sickling is inhibited by cyanate, an agent which reacts preferentially with N-terminal amino groups of proteins (Cerami and Manning, 1971).