Gluconeogenesis

Gluconeogenesis

The synthesis of glucose from non-carbohydrate precursors is known as gluconeogenesis. The major site of gluconeogenesis is liver. It usually occurs when the carbohydrate in the diet is insufficient to meet the demand in the body, with the intake of protein rich diet and at the time of starvation, when tissue proteins are broken down to amino acids.

Gluconeogenesis and glycolysis

Gluconeogenesis and glycolysis are opposing metabolic pathways and share a number of enzymes. In glycolysis, glucose is converted to pyruvate and in gluconeogenesis pyruvate is converted to glucose. However gluconeogenesis is not exact reversal of glycolysis.

There are three essentially irrevesible steps in glycolysis which are

In gluconeogenesis these three reactions are bypassed or substituted by the following news ones.

Reactions of gluconeogenesis

1. The formation of phosphoenol pyruvate begins with the carboxylation of pyruvate at the expense of ATP to form oxalo acetate.

Oxaloacetate is converted to phosphoenolpyruvate by phosphorylation with GTP, accompanied by a simultaneous decarboxylation.

2. Fructose 6-phosphate is formed from fructose 1,6-diphosphate by hydrolysis and the enzyme fructose 1,6-diphosphatase catalyses this reaction.

3. Glucose is formed by hydrolysis of glucose 6-phosphate catalysed by glucose 6-phosphatase.

Gluconeogenesis of amino acids

Amino acids which could be converted to glucose are called glucogenic amino acids. Most of the glucogenic amino acids are converted to the intermediates of citric acid cycle either by transamination or deamination.

Gluconeogenesis of Propionate

Propionate is a major source of glucose in ruminants, and enters the main gluconeogenic pathway via the citric acid cycle after conversion to succinyl CoA.

Gluconeogenesis of Glycerol

At the time of starvation glycerol can also undergo gluconeogenesis. When the triglycerides are hydrolysed in the adipose tissue, glycerol is released. Further metabolism of glycerol does not take place in the adipose tissue because of the lack of glycerol kinase necessary to phosphorylate it. Instead, glycerol passes to the liver where it is phosphorylated to glycerol 3-phosphate by the enzyme glycerol kinase.

This pathway connects the triose phosphate stage of glycolysis, because glycerol 3-phosphate is oxidized to dihydroxy acetone phosphate in the presence of NAD⁺ and glycerol 3-phosphate dehydrogenase. 

This dihydroxy acetone phosphate enters gluconeogenesis pathway and gets converted to glucose. Liver and kidney are able to convert glycerol to blood glucose by making use of the above enzymes.

Gluconeogenesis of lactic acid (Cori cycle)

The liver and skeletal muscles exhibit a special metabolic cooperation as far as carbohydrates are concerned by the way of a cycle of conversions known as Cori cycle.

In this cycle liver glycogen may be converted into muscle glycogen and vice versa and the major raw material of this cycle is lactate produced by the active skeletal muscles.

At the time of heavy muscular work or strenuous exercise, O₂ supply is inadequate in active muscles but the muscles keep contracting to the maximum. Hence, glycogen stored up in the muscle is converted into lactic acid by glycogenolysis followed by anaerobic glycolysis and thus lactate gets accumulated in the muscle. Muscle tissue lacks the enzyme glucose 6-phosphatase hence it is incapable of synthesizing glucose from lactic acid and the conversion take place only in the liver.

Lactate diffuses out of the muscle and enters the liver through blood. In the liver lactate is oxidised to pyruvate which undergoes the process of gluconeogenesis resulting in the resynthesis of glucose. The glycogen may be once again converted to glucose (glycogenolysis) and may be recycled to the muscle through the blood. The process of gluconeogenesis completes the cycle by converting glucose once again to muscle glycogen.