The energy-less red blood cell is lost: erythrocyte enzyme abnormalities of glycolysis

Abstract

The red blood cell depends solely on the anaerobic conversion of glucose by the Embden-Meyerhof pathway for the generation and storage of high-energy phosphates, which is necessary for the maintenance of a number of vital functions. Many red blood cell enzymopathies have been described that disturb the erythrocyte's integrity, shorten its cellular survival, and result in hemolytic anemia. By far the majority of these enzymopathies are hereditary in nature. In this review, we summarize the current knowledge regarding the genetic, biochemical, and struc- IntroductionThe moment the mature red blood cell leaves the bone marrow, it is optimally adapted to perform the binding and transport of oxygen and its delivery to all tissues. This is the most important task of the erythrocyte during its estimated 120-day journey in the bloodstream. The membrane, hemoglobin, and proteins involved in metabolic pathways of the red blood cell interact to modulate oxygen transport, protect hemoglobin from oxidant-induced damage, and maintain the osmotic environment of the cell. The biconcave shape of the red blood cell provides an optimal area for respiratory exchange. The latter requires passage through microcapillaries, which is achieved by a drastic modification of its biconcave shape, made possible only by the loss of the nucleus and cytoplasmic organelles and, consequently, the ability to synthesize proteins. 1 During their intravascular lifespan, erythrocytes require energy to maintain a number of vital cell functions. These include (1) maintenance of glycolysis; (2) maintenance of the electrolyte gradient between plasma and red cell cytoplasm through the activity of adenosine triphosphate (ATP)-driven membrane pumps; (3) synthesis of glutathione and other metabolites; (4) purine and pyrimidine metabolism; (5) maintenance of hemoglobin's iron in its functional, reduced, ferrous state; (6) protection of metabolic enzymes, hemoglobin, and membrane proteins from oxidative denaturation; and (7) preservation of membrane phospholipid asymmetry. Because of the lack of nuclei and mitochondria, mature red blood cells are incapable of generating energy via the (oxidative) Krebs cycle. Instead, erythrocytes depend on the anaerobic conversion of glucose by the Embden-Meyerhof pathway for the generation and storage of high-energy phosphates (Figure 1). Moreover, erythrocytes possess a unique glycolytic bypass for the production of 2,3-bisphosphoglycerate (2,3-DPG), the RapoportLuebering shunt. This shunt bypasses the phosphoglycerate kinase (PGK) step and accounts for the synthesis and regulation of 2,3-DPG levels that decrease hemoglobin's affinity for oxygen. 2 In addition, 2,3-DPG constitutes an energy buffer.A number of red blood cell enzymopathies have been described in the Embden-Meyerhof pathway. [3][4][5][6] The lack of characteristic changes in red blood cell morphology differentiates the glycolytic enzymopathies from erythrocyte membrane defects and most hemoglobinopathies. In general, red blood cell enzymopathies cause chronic n...

Impedance spectroscopy of solutions at physiological glucose concentrations

“…Since it was necessary to prevent both coagulation and glycolysis [4,5] in the blood container we had previously poured 1 g of potassium oxalate (99.98%, SigmaAldrich) and 1.25 g of sodium fluoride (99.99%, Sigma-Aldrich), acting as anticoagulant and glycolytic inhibitor, respectively [6]. We then measured the glucose concentration of the blood sample by two portable glucose meters (Freestyle, TheraSense, and Glucomen, Menarini Diagnostics).…”

AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency

“…The importance of glycolysis in RBCs is highlighted by the fact that mutations in nearly every glycolytic enzyme result in hemolytic anemia. 8 This is because mature RBCs lack mitochondria and rely almost exclusively on glycolysis to generate ATP.…”

Increased red cell turnover in a line of CD22‐deficient mice is caused by Gpi1c: A model for hereditary haemolytic anaemia

“…This result is inferred from the fact that the Gpi1 c polymorphism, which results in just 25% residual GPI1 activity, has been introduced from the ES cell strain used to generate these mice [35], and not removed during extensive backcrossing (since Gpi1 is located less than 3.5 Mbp from the targeted deletion in Cd22). GPI1 catalyses the interconversion of glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway [44]. Unlike other cells, RBCs are exquisitely sensitive to deficiency in glycolytic enzymes, since this metabolic pathway serves as the principal source of energy and reductive potential for the cell.…”