| Pyruvate may be directly converted to four different metabolites
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| Pyruvate is at a crossroads in metabolism. It may be converted in one step to lactate (lactate dehydrogenase), alanine (alanine aminotransferase, ALT), oxaloacetate (pyruvate carboxylase), and acetyl CoA (pyruvate dehydrogenase complex) (Fig. 13.3). Depending on metabolic circumstances, pyruvate may be routed toward gluconeogenesis (Chapter 12), fatty acid biosynthesis (Chapter 15) or the TCA cycle itself. Pyruvate carboxylase, like most other carboxylases, uses CO2 and the coenzyme biotin (Fig. 13.4), a water-soluble vitamin and ATP to drive the carboxylation reaction. The enzyme is a tetramer of identical subunits, each of which contains an allosteric site that binds acetyl-CoA, a positive heterotropic modifier. In fact, pyruvate carboxylase has an absolute requirement for acetyl-CoA; the enzyme does not work in its absence. An abundance of mitochondrial acetyl-CoA acts as a signal for the generation of additional oxaloacetate. For example, when lipolysis is stimulated, intra-mitochondrial acetyl-CoA levels rise, which allosterically activates pyruvate carboxylase to produce additional oxaloacetate for gluconeogenesis (Chapter 12).
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Lactic acid is measured in a clinical setting, because its accumulation can result in rapid death. Lactic acid is produced metabolically by the reversible reduction of pyruvate with NADH by the enzyme lactate dehydrogenase (LDH). Both lactate and pyruvate coexist in metabolic systems, and the ratio of pyruvate:lactate is roughly proportional to the cytosolic ratio of NAD+:NADH. Both lactate and pyruvate contribute to the acidity of biological fluid, however, lactate is usually present at higher concentrations and is more easily measured. Blood lactate may increase in chronic obstructive lung disease, and during intense exercise. Its measurement is usually indicated when there is metabolic acidosis, characterized by an elevated anion gap, [lcub ][Na+] - ([Cl-] + [CO2])[rcub ], indicating the presence of an unknown anion in plasma. Although rare, lactic acidosis can be caused by metabolic defects in energy-producing pathways, such as some of the glycogen storage diseases or in any enzyme in the pathways from pyruvate to the generation of ATP, including the pyruvate dehydrogenase complex, TCA cycle, electron transport system or ATP synthase. |
| Figure 13.3 Pyruvate is at the crossroads of metabolism. Pyruvate is readily formed from lactate or alanine. Acetyl-CoA and oxaloacetate are derived from pyruvate through the catalytic action of pyruvate dehydrogenase and pyruvate carboxylase, respectively. ADP, adenosine diphosphate. |
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