| ENZYMES AND REACTIONS OF THE TCA CYCLE
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| Figure 13.7 Intermediates and enzymes of the TCA cycle. |
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| DEFICIENCES IN PYRUVATE METABOLISM IN THE TCA CYCLE |
A 7-month-old-child showed progressive neurologic deterioration characterized by loss of coordination and muscle tone. He was unable to keep his head upright and had great difficulty moving his limbs, which were limp. He also suffered from unrelenting acidosis. Administration of thiamin had no effect. Measurements showed that he had elevated blood levels of lactate, α-ketoglutarate and branched-chain amino acids . Liver, brain, kidney, skeletal muscle, and heart were examined postmortem, and all gluconeogenic enzymes were shown to have normal activities, but both pyruvate dehydrogenase and α-ketoglutarate dehydrogenase were deficient. The defective component was shown to be dihydrolipoyl dehydrogenase (E3), which is a single gene component required by all of the α-ketoacid dehydrogenases. |
| Comments. This is an example of one of the many variants of Leigh's disease, which is a group of disorders that are all characterized by lactic acidosis. Lactic acid accumulates under anaerobic conditions or because of any enzyme defect in the pathway from pyruvate to the synthesis of ATP. In this case, there are defects in both the pyruvate dehydrogenase and α-ketoglutarate complexes, as well as other α-keto acid dehydrogenase complexes required for the catabolism of branched-chain amino acids. The failure of aerobic metabolism leads to increases in blood levels of lactate, α-ketoglutarate and branched-chain amino acids. Tissues dependent on aerobic metabolism, such as brain and muscle are most severely affected, so that the clinical picture includes impaired motor function, neurologic disorders and mental retardation. These diseases are rare, but deficiencies in pyruvate carboxylase and all of the components of the pyruvate dehydrogenase complex (PDH) have been described, including the associated kinase and phosphatase enzymes (Fig. 13.12). |
| The TCA cycle is a sequence of eight enzymatic reactions (Fig. 13.7), beginning with condensation of acetyl-CoA with
oxaloacetate (OAA) to form citrate. The oxaloacetate is regenerated on completion of the cycle. Of the four oxidations in the cycle, two involve decarboxylations. Three produce NADH and one produces FADH2. GTP, a high-energy phosphate, is produced at one step by substrate-level phosphorylation.
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