The acetate of acetyl CoA undergoes a stepwise oxidation to carbon dioxide and water in a cyclic pathway, the citric acid cycle, shown in Figures 5.17 and 5.18. This pathway is sometimes known as the Krebs cycle, after its discoverer, Sir Hans Krebs. For each mole of acetyl CoA oxidized in this pathway, there is a yield of:
This is a total of ~12 X ATP for each mole of acetyl CoA oxidized; as 2 mol of acetyl CoA are formed from each mol of glucose, this cycle yields ~24 X ATP for each mol of glucose oxidized.
Although it appears complex at first sight, the citric acid cycle is a simple pathway. A four-carbon compound, oxaloacetate, reacts with acetyl CoA to form a six-carbon compound, citric acid. The cycle is then a series of steps in which two carbon atoms are lost as carbon dioxide, followed by a series of oxidation and other reactions,
eventually reforming oxaloacetate. The CoA of acetyl CoA is released and is available for further formation of acetyl CoA from pyruvate.
Although, as discussed below (section 5.7), oxaloacetate is the precursor for gluconeogenesis, fatty acids and other compounds that give rise to acetyl CoA or acetoacetate cannot be used for net synthesis of glucose. As can be seen from Figure 5.18, although two carbons are added to the cycle by acetyl CoA, two carbons are lost as carbon dioxide in each turn of the cycle. Therefore, when acetyl CoA is the substrate, there is no increase in the pool of citric acid cycle intermediates, and therefore oxaloacetate cannot be withdrawn for gluconeogenesis.
a-Ketoglutarate dehydrogenase catalyses a reaction similar to that of pyruvate dehydrogenase — oxidative decarboxylation and formation of an acyl CoA derivative. Like pyruvate dehydrogenase, it is a thiamin diphosphate-dependent enzyme, and the reaction sequence is the same as that shown in Figure 5.16. However, thiamin deficiency does not have a significant effect on the citric acid cycle, because, as shown in Figure 5.19, a-ketoglutarate can undergo transamination to yield glutamate, which is decarboxylated to y-aminobutyric acid (GABA). In turn, GABA can undergo further metabolism to yield succinate. This pathway (sometimes called the GABA shunt) thus provides an alternative to a-ketoglutarate dehydrogenase in thiamin deficiency, so that oxidation of acetyl CoA and formation of ATP can continue.
The sequence of reactions between succinate and oxaloacetate is chemically the same as that involved in the ^-oxidation of fatty acids (section 5.5.2):
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