Pyruvate kinase synthesis and degradation by normal and pathologic cells during erythroid maturation

Abstract

Mature erythrocytes contain a specific isozyme of pyruvate kinase (R- PK) while immature erythroblasts coexpress R-PK and another isozyme, M2- PK. To determine what roles degradation and decreasing of synthesis played in the disappearance of M2-PK during erythroid maturation, M2-PK and R-PK synthesis and degradation were studied in erythroblasts from fetal liver and blood BFU-E-derived erythroblasts from healthy subjects, an erythroleukemic patient, and a patient with an erythrocyte PK hyperactivity associated with M2-PK persistence in mature erythrocytes. In normal erythroblasts, R-PK synthesis was constant throughout erythroid maturation, whereas M2-PK synthesis decreased to the point of becoming undetectable. R-PK degradation was very low, while M2-PK degradation was more pronounced and steady during erythroid maturation. In leukemic erythroblasts, total protein turnover was higher than in normal cells, but the M2-PK degradation rate was lower. In erythroblasts from the patient with M2-PK persistence in mature erythrocytes, M2-PK synthesis did not decline with cell maturation. In conclusion, our results emphasize the importance of the decrease of M2- PK synthesis in the disappearance of M2-PK during erythroid maturation. Further studies of patients with pathologic persistence of M2-PK synthesis will help in the understanding of this event involved in erythroid maturation.

Inherited Erythrocyte Pyruvate Kinase Deficiency in a Beagle Dog

“…Emrocyte pvrUv.1. over the entire observation period(8 months) but was associated with only mild exercise intolerance.Radiographs of the left femur initially did not show any obvious increased density of the bone marrow; however, at 1V2 years of age, when the dog suffered…”

Erythrocyte pyruvate kinase activation in red cell disorders

“…The importance of pyruvate kinase in red cells homeostasis is further supported in both mouse models and patients with pyruvate kinase deficiency by the evidence of chronic haemolytic anaemia associated with mild ineffective erythropoiesis [4–8]. Indeed, the reduction in lifespan of pyruvate kinase deficient erythrocyte due to severe oxidation, supports the close connection between energy and antioxidant systems, the large part of which are NADH dependent [4,9–11].…”

Novel potential therapeutics to modify iron metabolism and red cell synthesis in diseases associated with defective erythropoiesis

“…6,7 R-type pyruvate kinase is required for the survival of ma-ture red cells and to sustain the tricarboxylic acid cycle in erythroid precursors. [7][8][9] Erythropoietin (EPO) binds to the EPO receptor (EPOR) to regulate early-stage erythropoiesis, primarily by phosphorylation of the JAK2 kinase (Figure 2). 10 Phosphorylated JAK2 kinase is responsible for the activation of downstream pathways that regulate expression of genes that control proliferation, survival, and iron metabolism, such as the hormone erythroferrone (ERFE) (Figure 2).…”