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Red Cell Metabolism

The function of the red cell is to mediate the exchange of respiratory gases, oxygen and carbon dioxide, between the lungs and the tissues. The oxygen-transport protein Hemoglobin, accounting for about 90% of the dry weight of the mature cell is of fundamental importance in this process. At rest, we consume about 250 ml of oxygen and produce 200 ml of carbon dioxide per minute.  This increases tenfold during exercise.  If the respiratory gases by plasma in the absence of red blood cells, our activity would be reduced fifty fold. The iron in the heme moiety of hemoglobin must be maintained in the reduced (ferrous) state in order to bind oxygen reversibly, despite exposure to a variety of endogenous and exogenous oxidizing agents.  The red cell maintains several metabolic pathways to prevent the action of these oxidizing agents and to reduce the hemoglobin iron if it becomes oxidized. These mechanisms may fail under certain circumstances including  as found in red cells of sickle cell disease and thalassemia. Oxidized hemoglobin, methemoglobin is unable to bind oxygen. Known mechanisms for preventing or reversing oxidative denaturation of hemoglobin in the erythrocyte include methemoglobin reductases, superoxide dismutase, glutathione peroxidase, and catalase. Most of the physiologically important methemoglobin reduction occurs enzymatically but may be reduced nonenzymatically by certain compounds found in erythrocytes, such as ascorbic acid and glutathioneGlutathione is the principal reducing agent in erythrocytes and the essential cofactor in the glutathione peroxidase reaction.  Reduced glutathione (GSH) is a tripeptide (glutamyl-cysteinyl-glycine).  Two enzymatic reactions are required for the de novo synthesis of glutathione: glutamic acid + cysteine to glutamyl-cysteine followed by reaction with glycine to GSH.  In the course of reactions protecting hemoglobin from oxidation, GSH is oxidized, forming oxidized glutathione (GSSG), which consists of two GSH molecules joined by a disulfide linkage, and mixed disulfides with hemoglobin.  GSSG rapidly leaves the erythrocyte.  Thus, if a continuous supply of GSH is to be maintained, there is need for a system to reduce the oxidized forms of glutathione.  Such a system is provided by glutathione reductase, which catalyzes the reduction of GSSG by NADPH, a product of the pentose phosphate pathway.  Glutathione reductase also catalyzes the reduction of hemoglobin-glutathione disulfides, yielding GSH and hemoglobin.
Since there are no mitochondria in erythrocytes, these cells must depend on two much less efficient pathways for production of high-energy compounds, the anaerobic glycolytic (Embden-Meyerhof) pathway, which is also known as the hexose monophosphate shunt or the phosphogluconate pathway.  Under normal circumstances, about 90% of glucose entering the red cell is metabolized by the anaerobic pathway and 10% by the aerobic pathway.  Three important products are formed by the anaerobic glycolytic pathway:  NADH, a cofactor in the methemoglobin reductase reaction.  ATP, the major high-energy phosphate nucleotide that powers the cation pump; and 2,3-DPG, a regulator of hemoglobin function.  For each molecule of glucose that enters the pathway, two molecules of NADH are generated.  The yields of ATP and 2,3-DPG vary depending on the activity of the Rapoport-Luebering shunt.  The most important product of the pentose phosphate pathway in erythrocytes is reduced nicotinamide-adenine dinucleotide phosphate (NADPH).  The red cell lacks the reactions to utilize NADPH for energy; instead, NADPH, by serving as a cofactor in the reduction of oxidized glutathione (GSSG), is a major reducing agent in the cell and the ultimate source of protection against oxidative attack. The maintenance of a reducing state in the red cell is also essential to keep oxidant attack to other red cell (membrane) proteins and lipids in check. In addition ATP is needed for a myriad of active processes in the red cell from maintaining ion transport across the membrane and energy dependent enzyme reactions needed to maintain composition and organization of cytosol and red cell membrane.