Proteolysis in thalassemia: studies with protease inhibitors.

Intracellular proteolysis was studied in both thalassemic and normal reticulocytes. The main experiment comprised a short incubation of RBC with [3H] leucine, extensive washings, and further incubation in the presence of cold leucine and protein synthesis inhibitors. In the aliquots removed at various time intervals, the TCA-soluble radioactivity increased in contrast with the TCA-precipitable cpm, which decreased with no exception on prolonged incubation. Results were more pronounced when the initial incubation was carried out in the presence of a valine analog and were markedly inhibited when phenanthroline was added during the second phase of the experiment. Cell-free system gave similar results. "globin" containing analog residues were degraded easier than free alpha- and beta-globin chains; free alpha or beta Hb chains are not proteolysed. Thalassemic and normal reticulocytes did not show any significant differences. It is proposed that the thalassemic RBC contain efficient proteolytic mechanisms up to the end of their maturation, but these prove incapable of proteolysing the excess alpha chains completely. Chemical manipulations aiming to make those chains more digestible constitute another approach to the treatment of thalassemia.