Most amino acids are glucogenic, i.e. following deamination their carbon skeletons can be converted into glucose. Alanine and glutamine are the major amino acids exported from muscle for gluconeogenesis. Their relative concentrations in venous blood from muscle exceed their relative concentration in muscle protein, indicating considerable reshuffling of muscle amino acids to provide gluconeogenic substrates. As discussed in more detail in Chapter 18, alanine is converted directly into pyruvate by the enzyme alanine aminotransferase (alanine transaminase, ALT), and then gluconeogenesis proceeds as described for lactate. Other amino acids are converted into tricarboxylic acid cycle (TCA cycle) intermediates, then to malate for gluconeogenesis. Aspartate, for example, is converted into oxaloacetate by aspartate aminotransferase (aspartate transaminase, AST), and glutamate into α-ketoglutarate by glutamate dehydrogenase. Other glucogenic amino acids are converted by less direct routes into alanine or intermediates in the tricarboxylic acid cycle for gluconeogenesis. The amino groups of these amino acids are converted into urea, via the urea cycle, and the urea is excreted in urine (Chapter 18).
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| Glycerol enters gluconeogenesis at the level of triose phosphates (see Fig. 12.8). Following release of glycerol and fatty acids from adipose tissue into plasma, the glycerol is taken up into liver and phosphorylated by glycerol kinase, and then enters the gluconeogenic pathway as dihydroxyacetone phosphate. Only the glycerol component of fats can be converted into glucose. As discussed in Chapter 14, metabolism of fatty acids involves their conversion in two carbon oxidation steps to form acetyl CoA, which is then metabolized in the tricarboxylic acid cycle by condensation with oxaloacetate to form citrate. While the carbons of acetate are theoretically available for gluconeogenesis, two molecules of CO2 are eliminated during conversion of citrate into malate. Thus, although energy is produced during the tricarboxylic acid cycle, the two carbons invested for gluconeogenesis from acetyl CoA are lost as CO2. For this reason, acetyl CoA, and therefore, even-chain fatty acids, cannot serve as substrates for net gluconeogenesis. However, odd-chain and branched-chain fatty acids yield propionyl CoA, which can serve as a minor precursor for gluconeogenesis. Propionyl CoA is first carboxylated to methylmalonyl CoA, which undergoes racemase and mutase reactions to form succinyl CoA, a tricarboxylic acid cycle intermediate (see Chapter 14). Succinyl CoA is converted into malate, exits the mitochondrion and is oxidized to oxaloacetate. Following decarboxylation by PEPCK, the three carbons of propionate appear intact in PEP for gluconeogenesis.
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