2. Coenzymes: The PDHC contains five coenzymes that act as carriers or oxidants for the intermediates of the reactions shown in Figure 9.2. E1 requires thiamine pyrophosphate (TPP), E2 requires lipoic acid and CoA, and E3 requires FAD and NAD+. [Note: TPP, lipoic acid, and FAD are tightly bound to the enzymes and function as coenzymes–prosthetic groups (see p. 54).]
Deficiencies of thiamine or niacin can cause serious central nervous system problems. This is because brain cells are unable to produce sufficient ATP (via the TCA cycle) if the PDHC is inactive. Wernicke-Korsakoff, an encephalopathy-psychosis syndrome due to thiamine deficiency, may be seen with alcohol abuse (see p. 383).
3. Regulation: Covalent modifications by the two regulatory enzymes of the PDHC alternately activate and inactivate E1. PDH kinase phosphorylates and inactivates E1, whereas PDH phosphatase dephosphorylates and activates E1 (Fig. 9.3). The kinase itself is allosterically activated by ATP, acetyl CoA, and NADH. Therefore, in the presence of these high-energy products, the PDHC is turned off. [Note: It is actually the rise in the ATP/ADP (adenosine diphosphate), NADH/NAD+, or acetyl CoA/CoA ratios that affects enzymic activity.] Pyruvate is a potent inhibitor of PDH kinase. Therefore, if pyruvate concentrations are elevated, E1 will be maximally active. Calcium (Ca2+) is a strong activator of PDH phosphatase, stimulating E1 activity. This is particularly important in skeletal muscle, where Ca2+ release during contraction stimulates the PDHC and, thus, energy production. [Note: Although covalent regulation by the kinase and phosphatase is primary, the PDHC is also subject to product (NADH and acetyl CoA) inhibition.] 4. Deficiency: A deficiency of the α subunits of the tetrameric E1 component of the PDHC, although very rare, is the most common biochemical cause of congenital lactic acidosis. The deficiency results in a decreased ability to convert pyruvate to acetyl CoA, causing pyruvate to be shunted to lactate via lactate dehydrogenase (see p. 103). This creates particular problems for the brain, which relies on the TCA cycle for most of its energy and is particularly sensitive to acidosis. Symptoms are variable and include neurodegeneration, muscle spasticity, and, in the neonatal-onset form, early death. The gene for the α subunit is X linked, and because both males and females may be affected, the deficiency is classified as X-linked dominant. Although there is no proven treatment for PDHC deficiency, dietary restriction of carbohydrate and supplementation with thiamine may reduce symptoms in select patients.
Leigh syndrome (subacute necrotizing encephalomyelopathy) is a rare, progressive, neurodegenerative disorder caused by defects in mitochondrial ATP production, primarily as a result of mutations in genes that encode proteins of the PDHC, the ETC, or ATP synthase. Both nuclear and mitochondrial DNA can be affected.