Gluconeogenesis

Gluconeogenesis is the process by which glucose is synthesized from non-carbohydrate precursors under fasting conditions. The three main precursors for this process are lactate, glycerol, and glucogenic amino acids. Initially, the liver is the main organ responsible for gluconeogenesis, but during prolonged fasting, the kidney becomes the main organ.

While gluconeogenesis is the opposite of glycolysis, it is not a reversal of the process. This is because three steps of glycolysis are irreversible, and these steps are bypassed by alternative pathways. The control points of gluconeogenesis include reactions 1-4, which are used to bypass the tenth reaction of glycolysis.

Reaction 1 and 2

• These reactions occur in three stages: carboxylation of pyruvate to OAA, transport of OAA to the cytosol, and decarboxylation of OAA.
• These reactions require 1 ATP and 1 GTP.

Reaction 3-8

• These reactions are the reversal of glycolysis.
• Fructose-1,6-bisphosphate is formed at the end of step 8.

Reaction 9

• This reaction bypasses the third reaction of glycolysis.
• After this step, glucose-6-phosphate is produced by the reversal of glycolysis.
• 2 enzymes are required: glucose 6 phosphate translocase and glucose 6 phosphatase.

Regulation

• GNG and glycolysis are reciprocally regulated so that both do not occur at the same time.
• GNG is an expensive process requiring 6 ATP.
• However, to maintain a constant glucose supply, it is necessary.
• Regulation is by 3 mechanisms: allosteric regulation, hormonal regulation/covalent modification, and gene expression.

Covalent Modification

• Glucagon activates gluconeogenesis while inhibiting glycolysis.
• This means that hormones involved with gluconeogenesis are activated when phosphorylated and those favoring glycolysis are inactivated when phosphorylated.
• This is supported by allosteric regulation.

Allosteric Regulation

• During gluconeogenesis, fatty acids increase the acetyl co A levels in the cells.
• In addition, the cell is also in a high energy state.
• This prevents pyruvate from entering the TCA cycle.
• PFK 1 and fructose-1,6-bisphosphate are reciprocally regulated.
• F-2,6-BP and AMP are the main allosteric regulators.

Gene Expression

• This is a long-term mechanism of regulation unlike the other 2 mechanisms.
• Glucagon and glucocorticoids (cortisol) induce the expression of GNG enzymes like PEPCK and repress the expression of glycolytic enzymes.
• Insulin induces the expression of glycolytic enzymes and represses the expression of GNG enzymes.

Gluconeogenic Precursors

• Glycerol: Released from the hydrolysis of TAG. Glycerol and FA reach the liver via blood. FA convert to acetyl co A and produce energy. Glycerol enters gluconeogenesis as DHAP.
• Lactate: Lactate is produced from RBCs and exercising muscle. This is taken up by the liver and converted to pyruvate by LDH. This process is called the Cori cycle. Defects in the Cori cycle can cause lactic acidosis.

• Glucogenic amino acids: These mainly produce pyruvate or enter the TCA cycle from which they produce OAA. All amino acids except lysine and leucine are glucogenic. The main amino acid involved is alanine via the alanine cycle.

Gluconeogenesis is an essential process that occurs during fasting conditions to maintain a constant glucose supply in the body. The liver and kidney are the main organs responsible for this process, and it is regulated by a complex system of allosteric, hormonal, and gene expression mechanisms. The main precursors for gluconeogenesis are lactate, glycerol, and glucogenic amino acids. Understanding the mechanisms and regulation of gluconeogenesis is crucial for understanding metabolic disorders and developing treatments for them.