SUMMARY

• 18.1 Pyruvate Dehydrogenase Forms Acetyl Coenzyme A from Pyruvate

  Most fuel molecules enter the citric acid cycle as acetyl CoA. The link between glycolysis and the citric acid cycle is the oxidative decarboxylation of pyruvate to form acetyl CoA. In eukaryotes, this reaction and those of the cycle take place inside mitochondria, in contrast with glycolysis, which takes place in the cytoplasm. The enzyme complex catalyzing this reaction, the pyruvate dehydrogenase complex, consists of three distinct enzyme activities. Pyruvate dehydrogenase catalyzes the decarboxylation of pyruvate and the formation of acetyllipoamide. Dihydrolipoyl transacetylase forms acetyl CoA, and dihydrolipoyl dehydrogenase regenerates the active transacetylase. The complex requires five cofactors: thiamine pyrophosphate, lipoic acid, coenzyme A, NAD⁺, and FAD.

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• 18.2 The Pyruvate Dehydrogenase Complex Is Regulated by Two Mechanisms

  The irreversible formation of acetyl CoA from pyruvate is the regulatory point for the entry of glucose-derived pyruvate into the citric acid cycle. The pyruvate dehydrogenase complex is allosterically inhibited by acetyl CoA and NADH. The activity of the pyruvate dehydrogenase complex is stringently controlled by reversible phosphorylation by an associated kinase and phosphatase. High concentrations of ATP and NADH stimulate the kinase, which phosphorylates and inactivates the complex. ADP and pyruvate inhibit the kinase, whereas Ca²⁺ stimulates the phosphatase, which dephosphorylates and thereby activates the complex.

  The importance of the pyruvate dehydrogenase complex to metabolism, especially to catabolism in the central nervous system, is illustrated by beriberi. Beriberi is a neurological condition that results from a deficiency of thiamine, the vitamin precursor of thiamine pyrophosphate. The lack of TPP impairs the activity of the pyruvate dehydrogenase component of the pyruvate dehydrogenase complex. Arsenite and mercury are toxic because of their effects on the complex. These chemicals bind to the lipoic acid coenzyme of dihydrolipoyl dehydrogenase, inhibiting the activity of this enzyme.