6.4 GLUCONEOGENESIS

Gluconeogenesis Gluconeogenesis is the synthesis of glucose from noncarbohydrate and then conversion to glycogen The major substrates for gluconeogenesis are the glucogenic amino acids, lactate, glycerol, and propionate. Liver and kidney are the major tissues involved, since they contain a full complement of the necessary enzymes.

Importance Gluconeogenesis meets the needs of the body for glucose when carbohydrate is not available in sufficient amounts from the diet. A continual supply of glucose is necessary as a source of energy, especially for the nervous system and the erythrocytes. Failure of gluconeogensis is usually fatal. Below a critical blood glucose concentration, there is brain dysfunction, which can lead to coma and death. Glucose is also required in adipose tissue as a source of glyceride-glycerol, and it probably plays a role in maintaining the level of intermediates of the citric acid cycle in many tissues. Even under conditions where fat may be supplying most of the caloric requirement of the organism, there is always a certain basal requirement for glucose.

Glucose is the only fuel that will supply energy to skeletal muscle under anaerobic conditions. In addition, gluconeogenic mechanisms are used to clear the products of the metabolism of other tissues from the blood, e.g. lactate, produced by muscle and erythrocytes, and glycerols, which is continuously produced by adipose tissue. Gluconeogenesis involves glycolysis, the citric acid cycle, plus some special reactions

The energy barriers obstruct a simple reversal of glycolysis between pyruvate and phosphoenolpyruvate, between furctose 1,6 bisphosphate and furctose 6-phosphate, between glucose 6-phosphate and glucose, and between glucose 1-phosphate and glycogen. These reactions are all nonequilibrium, releasing much free energy as heat and therefore physiologically irreversible. These reactions are circumvented by the following special reactions.

A. Conversion of Pyruvate into Phosphoenolpyruvate: Pyruvate carboxylase, present in mitochondria, converts pyruvate to oxaloacetate in the presence of ATP, the B vitamin biotin, and CO2. The function of the biotin is to bind CO2 from bicarbonate onto the enzyme prior to the addition of the CO2 to pyruvate.

A second enzyme, phosphoenolpyruate carboxykinase, catalyzes the conversion of oxaloacetate to phosphoenolpyruvate. High energy phosphate in the form of GTP or ITP is requried in this reaction, and CO2 is liberated. Thus, with the help of these two enzymes catalyzing endergonic transformations and lactate dehydrogenase, lactate can be converted to phosphoenolpyruvate, overcoming the energy barrier between pyruvate and phosphoenolpyruvate.

B. Conversion of Fructose 1,6-Bisphosphate into Fructose 6- phosphate: The conversion of fructose1,6 bisphosphate to fructose 6-phosphate, necessary to achieve a reversal of glycolysis, is catalyzed by a specific enyzme, fructose-1,6 bisphosphatase. This enzyme is present in liver and kidney and in striated muscle. It is absent in heart muscle and smooth muscle.

C. Conversion of glucose 6-phosphate into Glucose: The conversion of glucose 6-phosphate to glucose is catalyzed by another specific phosphatase, glucose-6-phosphate.It’s presence allows a tissue to add glucose to the blood.

D. Conversion of glucose 6-phosphate into Glycogen: The break down of glycogen to glucose 1-phosphate is carried out by phosphorylase. The synthesis of glycogen involves an entirely different pathway through the formation of uridine diphosphate glucose and the activity of glycogen synthase. These key enzymes allow reversal of glycolysis to play a major role in gluconeogenesis, the relationships between gluconeogenesis and the glycolytic pathway.

After transamination or deamination, glucogenic amino acids form either pyruvate or members of the citric acid cycle. The reactions described above can account for the conversion of both glucogenic amino acids and lactate to glucose or glycogen. Thus, lactate forms pyruvate and enter the mitochondria before conversion to oxaloacetate and ultimate conversion to glucose. The source of pyruvate and oxaloacetate for gluconeogenesis is mainly amino acid catabolism.

Some amino acids are catabolized to pyruvate, oxaloacetate, or precursors of these. Muscle proteins may break down to supply amino acids. These are transported to liver where they are deaminated and converted to gluconeogenesis inputs. 

E. Conversion of propionate into succiny1coA: Propionate enters the main gluconeogenic pathway via the citric acid cycle after conversion to succiny1-coA. Propionate is first activated with ATP and CoA by an appropriate acy1-CoA synthetase. Propiony1 CoA formed undergoes a CO2 fixation reaction to form D-methylmalony1-CoA, catalyzed by propiony1-CoA carboxylase.

This reaction forms a malony1 derivative and requires the vitamin biotin as a coenzyme. D-Methylmalony1-CoA must be converted to its steroisomer, L-methylmalony1-CoA, by methylmalony1-coA racemase before its final isomerization to succiny1-CoA by the enzyme methlmalony1-CoA isomerase. It is converted into malate which is then converted into phosphoenol pyruvate and finally to glucose.