Gluconeogenesis

Steps, Reactions and Significance • Gluconeogenesis is the production of glucose from non-sugar precursors. • Gluconeogenesis, mainly occurs in the liver, and involves the synthesis of glucose from compounds that are not carbohydrates.

When a cell is growing on a hexose such as glucose, and obtaining glucose for polysaccharide synthesis, there is no problem.
But when the cell is growing on other carbon compounds, glucose must be synthesized. This process is called as gluconeogenesis.
Gluconeogenesis uses phosphoenolpyruvate, which is one of the intermediates of glycolysis, as starting material and travels backwards through the glycolytic pathway to form glucose.
However, it involves several enzymatic steps that do not occur in glycolysis; thus, glucose is not generated by a simple reversal of glycolysis alone.
The major precursors for gluconeogenesis are lactate, amino acids (which form pyruvate or TCA cycle intermediates), and glycerol (which forms DHAP).
The synthesis of 1 mole of glucose from 2 moles of lactate requires energy equivalent to about 6 moles of ATP.

Location of Gluconeogenesis

Liver, kidney, and intestine; not in skeletal muscle. The first reaction (catalyzed by pyruvate carboxylase) takes place in the mitochondria, whereas the rest of the reactions occur in the cytosol.

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Steps in Gluconeogenesis

Pyruvate carboxylase converts pyruvate to oxaloacetate in the mitochondrion.
Oxaloacetate is converted to malate or aspartate, which travels to the cytosol and is reconverted to oxaloacetate.
Phosphoenolpyruvate carboxykinase converts oxaloacetate to phosphoenolpyruvate.
Phosphoenolpyruvate forms fructose 1,6-bisphosphate by reversal of the steps of glycolysis.
Fructose 1,6-bisphosphatase converts fructose 1,6-bisphosphate to fructose-6-phosphate, which is converted to glucose-6-phosphate.
Glucose-6-phosphatase converts glucose-6-phosphate to free glucose, which is released into the blood.

Reactions involved in Gluconeogenesis

Conversion of pyruvate to phosphoenolpyruvate

In the liver, pyruvate is converted to phosphoenolpyruvate.

Pyruvate (produced from lactate, alanine, and other amino acids) is first converted to oxaloacetate by pyruvate carboxylase, a mitochondrial enzyme that requires biotin and ATP.
Oxaloacetate cannot directly cross the inner mitochondrial membrane. Therefore, it is converted to malate or to aspartate, which can cross the mitochondrial membrane and be reconverted to oxaloacetate in the cytosol.
Oxaloacetate is decarboxylated by phosphoenolpyruvate carboxykinase to form phosphoenolpyruvate. This reaction requires GTP.
Phosphoenolpyruvate is converted to fructose 1,6-bisphosphate by reversal of the glycolytic reactions.

Conversion of fructose 1,6-bisphosphate to fructose-6-phosphate • Fructose-1, 6-bisphosphate is converted to fructose-6-phosphate in a reaction that releases inorganic phosphate and is catalyzed by fructose-1,6-bisphosphatase. • Fructose-6-phosphate is converted to glucose 6- phosphate by the same isomerase used in glycolysis.
Conversion of glucose-6-phosphate to glucose

Glucose-6-phosphate releases inorganic phosphate, which produces free glucose that enters the blood. The enzyme involved is glucose 6-phosphatase.

Thus, the net requirements to make one glucose molecule are:

Two pyruvate.
Four ATP and two GTP.
Two NADH.
Six H2O

Significance of Gluconeogenesis Pathway

Gluconeogenesis meets the needs of the body for glucose when sufficient carbohydrate is not available from the diet or glycogen reserves.
Glycogen stored in adipose tissue and in skeletal muscle is converted to glucose by glycogenolysis. However the stored glycogen may not be sufficient during heavy exercise, diabetic conditions,or during fasting etc. so during shortage, glucose is synthesized by gluconeogenesis process.
A continual supply of glucose is necessary as a source of energy especially for the nervous system and erythrocytes.
Gluconeogenesis mechanism is used to clear the products of the metabolism of other tissues from the blood, eg: Lactate, produced by muscle and erythrocytes and glycerol, which is continuously produced by adipose tissue.