Molecular Aspects of Sickle Cell Disease

Sickle cell hemoglobin (hemoglobin S) contains valine instead of glutamic acid in position 6 of the β‐chain. Few detectable conformational differences exist between hemoglobin S and normal adult hemoglobin (hemoglobin A). Following loss of oxygen, sickle cell hemoglobin (hemoglobin S) self associates to form a liquid crystal phase which distorts the erythrocyte into the sickle shape thereby resulting in the clinical symptomology associated with sickle cell anemia. This gel contains deoxyhemoglobin S monomers and polymers in equilibrium. The polymerization process is known to have a negative temperature coefficient, to be pH dependent, and to be extremely dependent on hemoglobin S concentration. The polymerization of deoxyhemoglobin S appears to be entropically driven and occurs in two kinetic phases, a delay period and a rapid polymerization process. The polymer consists of tubules containing six or eight strands of deoxyhemoglobin S tetramers which align with one another. Each strand is would around the tubule with a pitch of about 3000 Å, but the precise nature of the intermolecular hemoglobin S contacts is not known. Subsequent alignment of the tubules occurs and results in the tactoids observed in (S/S) erythrocytes. While many of the details of polymer formation and structure remain to be elucidated, several attempts to chemically alter the sickling phenomenon have been carried out. As yet, however, no satisfactory chemical treatment has been discovered.