7.9. Gluconeogenesis

Gluconeogenesis is a glucose synthesis from substances of non-carbohydrate nature, which takes place mainly in the liver, and less intense - in the cortex of kidney and intestinal mucosa.

The function of gluconeogenesis is the maintenance of blood glucose during prolonged fasting and intense exercises. A constant supply of glucose as an energy source is particularly necessary for the nervous tissue and erythrocytes.

Gluconeogenesis substrates are pyruvic acid, lactic acid, glycerol, amino acids. Their inclusion in gluconeogenesis depends on the physiological state of the organism.

Most of the reactions of gluconeogenesis are the inverse of glycolysis. They are catalyzed by the same enzymes as the corresponding reactions of glycolysis.

Three reactions of glycolysis (hexokinase (1), phosphofructokinase (3), pyruvate kinase (10)) are irreversible, and during gluconeogenesis other enzymes operate on these stages.

Synthesis of glucose from the pyruvic acid.

The first step is the formation of phosphoenolpyruvate from pyruvic acid.

a) Carboxylation of pyruvic acid under the influence of pyruvate carboxylase leads to the formation of oxaloacetate in mitochondria:

Pyruvate carboxylase is mitochondrial biotin-dependent enzyme, allosteric activator of which is acetyl-KoA. Mitochondrial membrane is impermeable for oxaloacetate, so oxaloacetate in the mitochondria is converted to malate with the participation of mitochondrial NAD-dependent malate dehydrogenase:

Malate dehydrogenase

mitochondrial

Malate leaves the mitochondria through the mitochondrial membrane into the cytosol, where it is oxidized to oxaloacetate under the action of the cytoplasmic NAD-dependent malate dehydrogenase:

Malate dehydrogenase

cytoplasmic

b) in the cell cytosol decarboxylation and phosphorylation of oxaloacetate are proceeded to form phosphoenolpyruvate. The enzyme catalyzing this reaction is phosphoenolpyruvate carboxykinase:

Phosphoenolpyruvate carboxykinase

CO₂ is liberated. GTP is used in this reaction. So, on this stage 2 ATP equivalents are used. Then PEP undergoes the reversal of glycolysis until fructose-1,6-bisphosphate is produced.

The second stage is the conversion of fructose-1,6-bisphosphate into fructose-6-phosphate.

Phosphoenolpyruvate as a result of reversible reactions of glycolysis is converted to fructose-1,6-phosphate. Then an irreversible phosphofructokinase reaction of glycolysis is followed. Gluconeogenesis is bypassing this reaction:

F

Fructose bisphosphatase

ructose-1,6-bisphosphate + H₂O Fructose-6-phosphate

+ P_i

This enzyme required Mg²⁺ ions.

The third stage is the formation of glucose from fructose-6-phosphate.

Fructose-6-phosphate is converted to glucose-6-phosphate, which is dephosphorylated under the influence of glucose-6-phosphatase:

G

Glucose-6-phosphatase

lucose-6-phosphate + H₂O Glucose + P_i

Reaction is bypasses hexokinase reaction.

Enzymes of three irreversible stages of gluconeogenesis are regulatory enzymes.

The overall summary of gluconeogenesis is:

2 pyruvate + 2 NADH + 4 ATP + 2 GTP  glucose + 2 NAD+ + 4 ADP +

+ 2 GDP + 6 Pi