Molecular pathophysiology

Since the main physiological significance of the glycolytic pathway (see Figure 12.8 for an overview of glycolysis) in the red cell is to produce chemical energy in the form of ATP, the main consequence of any glycolytic enzymopathy is a shortage of energy supply. Since glycolytic enzymes are apparently present in cells in considerable excess, the 50% residual enzyme activity seen in heterozygotes does not become rate-limiting; thus, heterozygotes do not have hemolytic anemia, and that is why these enzymopathies show a recessive pattern of inheritance. As seen in Table 12.7, most of the mutations so far identified in the genes encoding glycolytic enzymes are of the missense type, causing single amino acid replacements. This is important, because the low level of residual enzyme activity can still support some metabolic flow through the glycolytic pathway, and helps explain how red cells survive in circulation, even though their lifespan is reduced. With respect to the precise reason why enzyme activity is reduced, we must consider at the protein level two basic mechanisms. (1) In the majority of cases loss of activity is probably due to a decreased stability of the protein. In such cases we would predict that other cells might be much less affected than red cells, because the former can compensate for decreased stability through increased synthesis of the enzyme. (2) In some cases the amino acid replacement may affect the active center of the enzyme, which in turn may affect either substrate binding (K ) or the catalytic rate of the enzyme (K ), or both: in this case other cells in which the rate of glycolysis is critical will be affected, as well as red cells.

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