Wednesday, September 25, 2013

RBC Metabolism Notes (Part 3) : Energy metabolism

  • Although the mature red cell contains the enzymes required for glycogen metabolism, the balance between synthesis and utilization is such that no significant amount of glycogen accumulates within the cell under normal circumstances. 

  • Glycogen may accumulate, however, in glycogen storage diseases types III and VI.

  • Lacking a storage compound, the normal erythrocytes must have constant access to glucose if its energy metabolism is to be sustained. 

  • As previously discussed, glucose enters the cell by means of a facilitated transport mechanism using a carrier. There is no requirement for insulin or other hormones, and transport is not ordinarily the rate-limiting factor in glucose utilization. 

  • Without mitochondria, erythrocytes must depend on two less efficient pathways for production of high-energy compounds, the anaerobic glycolytic (Embden-Meyerhof) pathway and the aerobic pentose phosphate pathway, also known as the hexose monophosphate pathway.
  • Under normal circumstances, about 90% of glucose entering the red cell is metabolized by the anaerobic pathway and 10% by the aerobic pathway. Under conditions of oxidative stress, however, the oxidative pentose phosphate pathway may account for up to 90% of glucose consumption.
  • 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 hemoglobin function

  • The yields of ATP and 2,3-DPG vary depending on the activity of Rapoport-Luebering shunt , a side pathway unique to the red cells. Two molecules of ATP are used in the early steps of glycolysis and a maximum of four molecules is produced late in the pathway. Thus, at maximum efficiency, a net yield of two molecules of ATP may be expected for each molecule of glucose metabolized. This net yield may be decreased, however, to the extent that 2,3-DPG is formed. For this reason, the DPG-forming step is sometimes referred to as an energy clutch.

  • Of the 11 enzymes in the glycolytic pathway, 3 appear to be particularly important in regulation of glycolytic rate. These are hexokinase, phosphofructokinase and pyruvate kinase. Hexokinase is the least active enzyme in the series and is therefore often rate limiting. it is inhibited by its product glucose-6-phosphate, and is stimulated by one of its substrates, Mg-ATP. The activity of phosphofructokinase is greatly affected by intracellular pH. Because the pH optimum of this enzyme is 8.0, the activity of this enzyme and the overall rate of glycolysis tend to increase with rises in phosphofructokinase may also be activated by the product of the further phosphorylation of fructose-6-phosphate. Pyruvate kinase is strongly inhibited by its product, ATP, and pyruvate kinase activity may therefore be related to the rate at which ATP is used in the cell's metabolic processes.

  • The importance of glycolysis to the red cell is illustrated by the manifestations of inherited disorders, in each of which the activities of one of the glycolytic enzymes is impaired. Under such circumstances, the viability of red cell is reduced, and hemolytic anemia results.

  • 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 use 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 utilization of NADPH is the main stimulus to the utilization of glucose-6-phosphate by the pathway. Redox reagents such as methylene blue, cysteine, ascorbate, and others induce an up to 20-fold increase in pentose metabolism, presumably by bringing about oxidation of glutathione. This metabolic flexibility allows the red cell to respond to unexpected oxidant challenge.

  • A second function of the pentose pathway is the conversion of hexose to pentose. For the most part, the latter are recycled into the glycolytic pathway; however, D-ribose-5-phosphate may be used for nucleotide synthesis.

    Next, We will discuss about the maturation of RBC where we will discuss about the role of folic acid and Vitamin B12 in DNA synthesis.

    (Source:  Wintrobe's Textbook of Hematology; Tietz's Textbook of Clinical Chemistry)
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