Models of Erythrocyte Metabolism

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Over the last 25 years many mathematical models of erythrocyte metabolism have been developed/4-7 These have been very successful in identifying the key features of the regulation and control of the metabolism of the cell. Indeed the erythrocyte is the best modelled of all biochemical systems and there are a number of reasons for this. The first is the ease of obtaining them by simple venipuncture. Second, the erythrocyte has relatively simple metabolism as a result of lacking mitochondria and other organelles (Fig. 7.1).

Erythrozytenstoffwechsel

Figure 7.1. Erythrocyte metabolism. The best known physiological function of the erythrocyte is the facilitation of oxygen transport throughout the body. In response to this task, the erythrocyte has evolved into a highly specialized but metabolically simple cell. The mature human erythrocyte has lost all organelles and hence its metabolism is primarily reduced to the glycolytic and pentose phosphate pathways.These two pathways generate the ATP and reducing equivalents that keep the cell functionally active. A peculiar feature of glycolysis in erythrocytes is the possession of an alternative pathway for carbon flux via 1,3-bisphosphoglycerate (1,2-BPG). This pathway, known as the 2,3-BPG or Rapoport-Luebering shunt, bypasses phosphoglycerate kinase by converting 1,3-BPG to 2,3-BPG in the metabolic pathway. The enzymes are denoted by: AK (adenylate kinase); Ald (aldolase); BPGP (2,3-BPG phosphatase); BPGS (2,3-BPG synthase); G6PDH (glucose-6-phosphate dehydrogenase); GAPDH (glyceraldehyde-3-phosphate dehydrogenase); GPI (glucosephosphate isomerase); HK (Hexokinase); kATPase (non-glycolytic energy consumption); kox (reduction processes consuming GSH); koxNADH

Figure 7.1. Erythrocyte metabolism. The best known physiological function of the erythrocyte is the facilitation of oxygen transport throughout the body. In response to this task, the erythrocyte has evolved into a highly specialized but metabolically simple cell. The mature human erythrocyte has lost all organelles and hence its metabolism is primarily reduced to the glycolytic and pentose phosphate pathways.These two pathways generate the ATP and reducing equivalents that keep the cell functionally active. A peculiar feature of glycolysis in erythrocytes is the possession of an alternative pathway for carbon flux via 1,3-bisphosphoglycerate (1,2-BPG). This pathway, known as the 2,3-BPG or Rapoport-Luebering shunt, bypasses phosphoglycerate kinase by converting 1,3-BPG to 2,3-BPG in the metabolic pathway. The enzymes are denoted by: AK (adenylate kinase); Ald (aldolase); BPGP (2,3-BPG phosphatase); BPGS (2,3-BPG synthase); G6PDH (glucose-6-phosphate dehydrogenase); GAPDH (glyceraldehyde-3-phosphate dehydrogenase); GPI (glucosephosphate isomerase); HK (Hexokinase); kATPase (non-glycolytic energy consumption); kox (reduction processes consuming GSH); koxNADH

(reducing processes requiring NADH); Lactonase (8-gluconolactonase); LDH (lactate dehydrogenase; note that the model also includes an NADPH-dependent lactate dehydrogenase); PFK (phosphofructokinase); PGK (phosphoglycerate kinase); 6PGDH (6-phosphogluconate dehydrogenase); PGM (phosphoglycerate mutase); PK (pyruvate kinase); R5PI (ribose-5-phosophate isomerase); Ru5E (ribulose-5-phosphate epimerase); TA (transaldolase); TK (transketolase); TPI (triose phosphate isomerase). Metabolites: 1,3-BPG (1,3-bisphosphoglycerate); 2,3-BPG (2,3-bisphosphoglycerate); Ery4P (erythrose 4-phosphate); Fru(1,6)P2 (fructose 1,6-bisphosphate); Fru6P (fructose 6-phosphate); Glc (glucose); Glc6P (glucose 6-phosphate); GraP (glyceraldehyde 3-phosphate); GrnP (dihydroxyacetone phosphate); Lac (lactate); Lace (extracellular lactate); Pi (inorganic phosphate); Pie (extracellular inorganic phosphate); PEP (phosphenolpyruvate); 2-PGA (2-phosphoglycerate); 3-PGA (3-phosphoglycerate); 6-PG (6-phosphogluconate); 6-PGL (6-phosphoglucolactone); Pyr (pyruvate); Pyre (extracellular pyruvate); Rib5P (ribose 5-phosphate); Ru5P (ribulose 5-phoshate); Sed7P (sedoheptulose 7-phosphate); Xu5P (xylulose 5-phosphate).

The model presented in this chapter was developed with the primary aim of illuminating our understanding of the regulation and control of the 2,3-bisphosphoglycerate (2,3-BPG) concentration. 2,3-BPG is important in regulating blood oxygen transport and delivery. In clinical and environmental conditions where oxygen transport has been compromised, such as anemia, congenital heart disease, and high altitude, the concentration of 2,3-BPG is often elevated well above normal values. 2,3-BPG is a heterotropic allosteric effector of oxygen binding by hemoglobin (Hb). By binding preferentially to the deoxygenated form of Hb, it decreases the apparent affinity of Hb for O2. Although the interactions between Hb and 2,3-BPG had been known for more than 30 years prior to the development of this model, the precise regulatory features of 2,3-BPG metabolism were still an issue of much debate until recently.

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