Gluconeogenesis

Gluconeogenesis is the biosynthesis of glucose from nonionic compounds, such as, Pyruvate, Lactate, Glucogenic amino acids, glycerol, propionate. About 90% of gluconeogenesis occurs at liver and about 10% of gluconeogenesis occurs at kidney. Gluconeogenesis involves glycolysis, citric acid cycle and some special reactions.

The first bypass is conversion of Pyruvate into Phosphoenolpyruvate. Reversal of the reaction catalyzed by Pyruvate kinase in glycolysis involves two endothermic reactions. Phosphoenolpyruvate is formed from pyruvate by way of Oxaloacetate through the action of Pyruvate carboxylation and phosphoenolpyruvate carboxy kinase. Oxaloacetate, the product of the pyruvate carboxylase reaction is reduced to Malate inside the mitochondrion for transport to the cytosol. Then the second enzyme, phosphoenolpyruvate carboxy kinase catalyzes the decarboxylation and phosphorylation oxaloacetate to phosphoenolpyruvate using GTP as the phosphate doner.

The second bypass is the hydrolysis of the Fructose 1,6-bisphosphate into Fructose 6-Phosphate. The enzyme which is involved for this reaction is Fructose 1,6-bisphosphertase. It is an allosteric enzyme, that participate in the regulation of gluconeogenesis.

The third bypass is the hydrolysis of Glucose 6-phosphate into Glucose. Hydrolysis of Glucose 6-phosphate by glucose 6-phosphotase bypasses the irreversible hexokinase reaction, and provides and energetically favorable pathway for the formation of free glucose. Liver and kidney are the only organ that release free glucose from glucose 6-phosphate. Muscle and adipose tissue lack of glucose 6-phosphotase, and therefore muscle glycogen cannot be used to maintain blood glucose level.

 

Substrates for gluconeogenesis

Glycerol is released during the hydrolysis of triacylglycerols in adipose tissue. Amino acids are derived from hydrolysis of tissue proteins are the main source of glucose during fasting. Lactate is released to blood during exercising skeletal muscles and by cells that lack mitochondria, such as red blood cells.

In the cori cycle, Lactate is produced by the Lactate dehydrogenase reaction is released to the blood stream and transported to the liver where it is converted to glucose. The glucose is then returned to the blood for use by muscle as an energy source and to replenish glycogen stores.

 

Regulation of gluconeogenesis

Glucagon

Changes in the rate of enzyme synthesis.

-        The effect of glucocorticoids and glucagon stimulated cAMP which induce synthesis of the key enzyme responsible for gluconeogenesis.

Covalent modification by reversible phosphorylation

-        Activates cAMP dependent protein kinase leading to phosphorylation and inactivation of pyruvate kinase.

Allosteric affect

-        Glucagon lowers the level of Fructose 2,6-bisphosphate

 

Substrate availability

Allosteric activation by acetyl CoA – allosteric activation of hepatic pyruvate carboxylase by acetyl CoA occurs during fasting.

Allosteric inhibition by AMP – Fructose 1,6 – bisphosphates is inhibited by AMP.

 

Importance of gluconeogenesis

 Gluconeogenesis supplies energy to vital organs (brain, heart, kidney medulla) which need continuous supply of glucose as an energy source. Glucose is the only fuel that supplies the energy to skeleton muscle under anerobic conditions. All other carbohydrates can be synthesized from glucose. In fasting more than a day, gluconeogenesis supplies the intermediates of citric acid cycle. Glucose is essential in adipose tissue as a source of glycerol. It is important to clear products from other tissues or blood. Example – Lactate from muscles.