Gluconeogenesis the synthesis of glucose from

To a considerable extent the plasma concentration of glucose is maintained in short-term fasting by the use of glycogen, and by releasing free fatty acids from adipose tissues and ketone bodies from the liver, which are preferentially used by muscle, so sparing such glucose as is available for use by the brain and red blood cells.

However, the total body content of glycogen would be exhausted within 12—18 hours of fasting if there were no other source of glucose. This is the process of gluconeogenesis — the synthesis of glucose from non-carbohydrate precursors: amino acids from the breakdown of protein and the glycerol of triacylglycerols. It is important to note that, although acetyl CoA, and hence fatty acids, can be synthesized from pyruvate (and therefore from carbohydrates), the decarboxylation of pyruvate to acetyl CoA cannot be reversed. Pyruvate cannot be formed from acetyl CoA. As two molecules of carbon dioxide are formed for each two-carbon acetate unit metabolized in the citric acid cycle (see Figure 5.18), there can be no net formation of oxaloacetate from acetate. It is not possible to synthesize glucose from acetyl CoA, and fatty acids and ketone bodies cannot serve as a precursor for glucose synthesis under any circumstances,

The pathway of gluconeogenesis is essentially the reverse of the pathway of glycolysis, shown in Figure 5.10. However, at three steps there are separate enzymes involved in the breakdown of glucose (glycolysis) and gluconeogenesis. As discussed in section 5.4.1, the reactions of pyruvate kinase, phosphofructokinase and hexokinase cannot readily be reversed (i.e. they have equilibria which are strongly in the direction of the formation of pyruvate, fructose bisphosphate and glucose 6-phosphate respectively).

There are therefore separate enzymes, under distinct metabolic control, for the reverse of each of these reactions in gluconeogenesis:

  • Pyruvate is converted to phosphoenolpyruvate for glucose synthesis by a two-step reaction, with the intermediate formation of oxaloacetate. As shown in Figure 5.31, pyruvate is carboxylated to oxaloacetate in an ATP-dependent reaction in which the vitamin biotin (section 11.12) is the coenzyme. This reaction can also be used to replenish oxaloacetate in the citric acid cycle when intermediates have been withdrawn for use in other pathways, and is involved in the return of oxaloacetate from the cytosol to the mitochondrion in fatty acid synthesis — see Figure 5.26. Oxaloacetate then undergoes a phosphorylation reaction, in which it also loses carbon dioxide, to form phosphoenolpyruvate. The phosphate donor for this reaction is GTP; as discussed in section 5.4.4, this provides regulation over the use of oxaloacetate for gluconeogenesis if citric acid cycle activity would be impaired.
  • Fructose bisphosphate is hydrolysed to fructose 6-phosphate by a simple hydrolysis reaction catalysed by the enzyme fructose bisphosphatase.
  • Glucose 6-phosphate is hydrolysed to free glucose and phosphate by the action of glucose 6-phosphatase.
Figure 5.31 Reversal of the reaction of pyruvate kinase for gluconeogenesis — pyruvate carboxylase and phosphoenolpyruvate carboxykinase.

The other reactions of glycolysis are readily reversible, and the overall direction of metabolism, either glycolysis or gluconeogenesis, depends mainly on the relative activities of phosphofructokinase and fructose bisphosphatase, as discussed in section 10.2.2.

As discussed in section and section 9.3.2, many of the products of amino acid metabolism can also be used for gluconeogenesis, as they are sources of pyruvate or one of the intermediates in the citric acid cycle, and hence give rise to oxaloacetate. The requirement for gluconeogenesis from amino acids in order to maintain a supply of glucose explains why there is often a considerable loss of muscle in prolonged fasting or starvation, even if there are apparently adequate reserves of adipose tissue to meet energy needs.

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