Gluconeogenesis Overview

Gluconeogenesis Overview

• Gluconeogenesis is the process of producing glucose from non-carbohydrate precursors.
• This process is essential when dietary glucose is insufficient.
• Specific tissues, such as the brain, red blood cells, and exercising muscles, require a constant supply of glucose.

Function of Gluconeogenesis

• Gluconeogenesis produces glucose when dietary or circulating glucose levels are insufficient for tissue needs
• This happens during starvation, prolonged fasting, or abnormal glucose homeostasis.

Sources of Glucose

• Food
• Stored glycogen
• Non-carbohydrate sources (e.g., glycerol, lactate, amino acids)

Need for Glucose

• Energy: While not the only source, glucose is the preferred source for some tissues (e.g., brain)
• Synthesis of ribose for nucleotide production: (e.g., DNA/RNA)
• Synthesis of glycoproteins and glycolipids.

When Gluconeogenesis Occurs

• When blood glucose levels drop too low to maintain cell/tissue demands.

Substrates for Gluconeogenesis

• Glycerol: Derived from triglycerides. The liver phosphorylates glycerol to glycerol-3-phosphate. It's then oxidized to dihydroxyacetone phosphate, an intermediate in glycolysis. This traps the glycerol molecule within the cell.
• Lactate: Derived from anaerobic glycolysis (e.g., exercising muscle). Lactate is transported to the liver and eventually converted back to glucose—part of the Cori cycle.
• Amino acids: Especially alanine, derived from protein breakdown. Catabolism produces α-keto acids like α-ketoglutarate, creating oxaloacetate—a crucial precursor to phosphoenolpyruvate.

Glycolysis vs. Gluconeogenesis

• Glycolysis and gluconeogenesis are not simply reverse processes.
• Gluconeogenesis uses unique steps to bypass the three irreversible steps of glycolysis.

Pyruvate to Phosphoenolpyruvate

• Pyruvate carboxylase converts pyruvate to oxaloacetate.
• Oxaloacetate is decarboxylated and phosphorylated by PEP carboxykinase to form phosphoenolpyruvate..

Conversion of PEP to Fructose 1,6-Bisphosphate

• The reactions involved reverse the direction of glycolysis.

Dephosphorylation of Fructose 1,6-Bisphosphate

• Fructose 1,6-bisphosphatase hydrolyzes fructose 1,6-bisphosphate bypassing the PFK-1 step in glycolysis.
• This step is hormonally regulated (e.g., high AMP, low insulin/high glucagon ratios).

Dephosphorylation of Glucose 6-Phosphate

• Glucose 6-phosphatase removes the phosphate group from glucose 6-phosphate, producing free glucose.
• The liver and kidneys are the only organs capable of this process

Regulation of Gluconeogenesis

• Glucagon plays a crucial role, influencing allosteric effectors and enzyme activity (e.g., phosphorylation of key enzymes).
• Substrate availability (e.g., amino acids, glycerol) also impacts the rate of gluconeogenesis.
• Hormonal regulation (e.g., insulin/glucagon ratio) has a significant effect.