CLINICAL CASES
213
As shown in Figure 23-1, 2 mol of ATP are formed per mole of glucose
metabolized by the glycolytic cycle. The primary final product of glucose
metabolism by glycolysis in the RBC is not pyruvate, as in other tissues most
of the time, but lactate. Since RBCs have no mitochondria, NAD+ cannot be
regenerated by shuttling NADH produced in glycolysis into the mitochondrial
electron transport system. Therefore, the only option to continue glycolysis is
to regenerate NAD+ from NADH by reducing pyruvate to lactate in the lactate
dehydrogenase reaction. But lactate is not the sole product of RBC glycolysis.
Methemoglobin reductase uses some of the NADH produced by glycolysis to
reduce methemoglobin (Fe3+) back to active hemoglobin (Fe2+) capable of
binding O2 for transport to the tissues. Thus the final products are a mixture of
lactate and pyruvate with lactate being the primary product.
In tissues other than the RBC, pyruvate has alternative metabolic fates that,
depending on the tissue, include gluconeogenesis, conversion to acetyl-CoA
by pyruvate dehydrogenase for further metabolism to CO2 in the tricarboxylic
acid (TCA) cycle, transamination to alanine or carboxylation to oxaloacetate
by pyruvate carboxylase (Table 23-1). In the RBC, however, the restricted
enzymatic endowment precludes all but the conversion to lactate. The pyruvate
and lactate produced are end products of RBC glycolysis that are transported
out of the RBC to the liver where they can undergo the alternative metabolic
conversions described above.
How does compromise of pyruvate kinase activity lead to anemia? Pyruvate
kinase lies at the end of the glycolytic pathway in RBCs followed only by lac-
tate dehydrogenase. In any linked pathway where the product of one reaction
is the substrate for the next reaction a compromise in one reaction affects the
entire pathway. The RBC depends exclusively on glycolysis to produce ATP to
discharge all energy-requiring tasks. Pyruvate kinase activity is critical for the
pathway and therefore critical for energy production. If ATP is not produced
in amounts sufficient to meet the energy demand, then those functions are
compromised. Energy is required to maintain the Na+/K+ balance within the
RBC and to maintain the flexible discoid shape of the cell. In the absence of
sufficient pyruvate kinase activity and therefore ATP, the ionic balance fails,
and the membrane becomes misshapen. Cells reflecting pyruvate kinase insuf-
ficiency rather than a change in membrane composition are removed from the
circulation by the macrophages of the spleen. This results in an increased num-
ber of circulating reticulocytes and possibly bone marrow hyperplasia, which
is a biological response to lowered RBC count as a result of hemolysis of
erythrocytes.
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