Gluconeogenesis Overview

Gluconeogenesis

• Gluconeogenesis is the process of synthesizing glucose from non-carbohydrate precursors.
• It is essential for maintaining blood glucose levels during fasting or starvation.
• Three key irreversible reactions in glycolysis are bypassed in gluconeogenesis:
  • Hexokinase (or Glucokinase)
  • Phosphofructokinase
  • Pyruvate Kinase
• Gluconeogenesis uses unique key enzymes distinct from glycolysis.

Gluconeogenesis Key Enzymes

• Pyruvate carboxylase converts pyruvate to oxaloacetate.
• PEP carboxykinase converts oxaloacetate to phosphoenolpyruvate.
• Fructose 1,6 bisphosphatase converts fructose 1,6 bisphosphate to fructose 6 phosphate.
• Glucose 6-phosphatase converts glucose 6-phosphate to glucose.

Gluconeogenic Precursors

• Intermediates of glycolysis: These can be used to synthesize glucose.
• Intermediates of the citric acid cycle: These can be converted to oxaloacetate and then to glucose.
• Lactate: Lactic acid produced during anaerobic glycolysis in cells like red blood cells and skeletal muscles is transported to the liver and converted to glucose (Cori cycle).
• Glycerol: Derived from triacylglycerol in adipose tissue, glycerol is converted to dihydroxyacetone phosphate (DHAP) and then to glucose.
• Glucogenic amino acids: Deaminated to form α-ketoacids, which are then converted to pyruvate or citric acid cycle intermediates before being synthesized into glucose.

Cori Cycle

• The Cori cycle is a metabolic pathway involving the liver and muscles.
• Muscles produce lactate during intensive exercise.
• Lactate is transported to the liver and converted to glucose.
• The newly synthesized glucose is returned to the muscles for energy production.

Clinical Applications of Gluconeogenesis

• Fructose 1,6 bisphosphatase deficiency: This genetic disorder leads to a deficiency in the enzyme responsible for the conversion of fructose 1,6 bisphosphate to fructose 6 phosphate. It results in fasting hypoglycemia and lactic acidosis.
• Hypoglycemia in neonates: Premature babies are more susceptible to hypoglycemia due to their immature gluconeogenesis enzymes and low adipose tissue mass.

Glucogenic Amino Acids

• Glucogenic amino acids are those that can be converted into glucose via gluconeogenesis.
• Examples include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, methionine, proline, serine, threonine, and valine.
• These amino acids are often deaminated (removal of an amino group) to yield α-ketoacids, which can then enter the gluconeogenic pathway.