Gluconeogenesis Produces Glucose from Pyruvate

The conversion of pyruvate to phosphoenolpyruvate in gluconeogenesis takes place in two steps. The first step is the reaction of pyruvate and carbon dioxide to give oxaloacetate. This step requires energy, which is available from the hydrolysis of ATP. 

The enzyme that catalyzes this reaction is pyruvate carboxylase, an allosteric enzyme found in the mitochondria. Acetyl-CoA is an allosteric effector that activates pyruvate carboxylase. If high levels of acetyl-GoA are present (in other words, if there is more acetyl-GoA than is needed to supply the citric acid cycle), pyruvate (a precursor of acetyl-GoA) can be diverted to gluconeogenesis. (Oxaloacetate from the citric acid cycle can frequendy be a starting point for gluconeogenesis as well.) Magnesium ion (Mg +) and biotin are also required for effective catalysis. We have seen Mg + as a cofactor before, but we have not seen biotin, which requires some discussion. 

The conversion of oxaloacetate to phosphoenolpyruvate is catalyzed by the enzyme phosphoenolpyruvate carboxykinase (PEPCK), which is found in the 

The successive carboxylation and decarboxylation reactions are both close to equilibrium (they have low values of their standard free energies) as a result, the conversion of pyruvate to phosphoenolpyruvate is also close to equilibrium (AG° = 2.1 kj mol = 0.5 kcalmoh ). A small in crease in the level of oxaloacetate can drive the equilibrium to the right, and a small increase in the level of phosphoenolpyruvate can drive it to the left. A concept well known in general chemistry, the law of mass action, relates the concentrations of reactants and products in a system at equilibrium. Changing the concentration of reactants or products causes a shift to reestablish equilibrium. A reaction proceeds to the right on addition of reactants and to the left on addition of products. 

I FIGURE 18.9 Pyruvate carboxylase catalyzes a compartmentalized reaction. Pyruvate is converted to oxaloacetate in the mitochondria. Because oxaloacetate cannot be transported across the mitochondrial membrane, it must be reduced to malate, transported to the cytosol, and then oxidized back to oxaloacetate before gluconeogenesis can continue. 

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GlUCOneogenesis This pathway produces glucose from carbon-containing molecules that are not carbohydrates. For example, it can convert pyruvate into glucose, the reverse of glycolysis. 

This reaction, which produces oxaloacetate from pyruvate, provides a connection between the amphibolic citric acid cycle and the anabolism of sugars by gluconeogenesis. On this same topic of carbohydrate anabolism, we should note again that pyruvate cannot be produced from acetyl-GoA in mammals. Because acetyl-GoA is the end product of catabolism of latty acids, we can see that mammals could not exist with fats or acetate as the sole carbon source. The intermediates of carbohydrate metabolism would soon be depleted. Garbohydrates are the principal energy and carbon source in animals (Figure 19.11), and glucose is especially critical in humans because it is the preferred fuel for our brain cells. Plants can carry out the conversion of acetyl-GoA to pyruvate and oxaloacetate, so they can exist without carbohydrates as a carbon source. The conversion of pyruvate to acetyl-GoA does take place in both plants and animals (see Section 19.3). 

The free glucose produced by this reaction is supplied to the blood from the tissues. As exemplified by gluconeogenesis, one may easily envision the economical organization of these metabolic routes, since, apart from four special gluconeogenesis enzymes-pyruvate carboxylase, phosphopyruvate carboxylase, fructose bisphosphatase, and glucose 6-phosphatase-individual glycolytic enzymes are also used in the gluconeogenesis. 

The pyruvate produced at point (3) can be used to produce energy within the liver or for gluconeogenesis. Pyruvate produces energy when it is oxidized in the mitochondria by the Krebs cycle. It is used for gluconeogenesis when it is converted in the mitochondria to OAA, then to malate, which, after exit from the mitochondria, is converted to PEP and eventually to glucose. 

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