Gluconeogenesis

Carbohydrate Metabolism

Overview

• Carbohydrate Metabolism is divided into two main categories:

  • Glycogen Metabolism (Polysaccharide Metabolism)

  • Includes:

    • Glycogen breakdown (catabolism)

    • Glycogen synthesis (anabolism)

  • Glucose Metabolism (Monosaccharide Metabolism)

  • Includes:

    • Glucose breakdown (catabolism):

    • Glycolysis

    • The Citric Acid Cycle (Krebs Cycle)

    • Pentose Phosphate Pathway

    • Glucose synthesis (anabolism):

    • Gluconeogenesis

    • Photosynthesis

      • Light Reaction

      • Dark Reaction - Calvin Cycle

Gluconeogenesis

Definition

• Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors.

Major Precursors

• The primary precursors for gluconeogenesis include:

  • Lactate

  • Amino Acids

  • Glycerol

Major Site

• Liver: The significant site for gluconeogenesis, while glycolysis mainly occurs in the muscle and brain.

Importance

• Particularly crucial during fasting or starvation since glucose is:

  • The primary fuel for the brain

  • The only fuel for red blood cells

Pathway Dynamics

• Gluconeogenesis and Glycolysis operate in opposite directions:

  • However, gluconeogenesis is not just the reverse of glycolysis.

• Many reactions in both pathways are reversible, but specific irreversible reactions in glycolysis must be bypassed in gluconeogenesis.

  • Three key irreversible reactions in glycolysis are:

  • Hexokinase

  • Phosphofructokinase

  • Pyruvate Kinase

Detailed Bypass Mechanisms

Bypass of Pyruvate Kinase

1. Pyruvate Kinase Reaction:

   • Catalyzes the reaction:

     • $ext{phosphoenolpyruvate} + ext{ADP} <br>ightarrow ext{pyruvate} + ext{ATP}$

2. Bypass Mechanism:

   • Two energy-consuming steps are required to bypass this reaction:

   1. Pyruvate Carboxylase

      • Converts pyruvate to oxaloacetate

   2. Phosphoenolpyruvate Carboxykinase (PEPCK)

      • Converts oxaloacetate to phosphoenolpyruvate (PEP)

   • Carboxylation uses a biotin cofactor and occurs in the mitochondria.

   • Since oxaloacetate cannot be directly transported into or out of the mitochondria, it is shuttled into the cytoplasm via malate.

   • Oxaloacetate is reduced to malate and then transported. In the cytoplasm, malate is reoxidized back to oxaloacetate.

Bypass Details and Enzymes

• Second Bypass Step:

  • Phosphoenolpyruvate Carboxykinase converts oxaloacetate to PEP

  • Involves phosphorylation from GTP and decarboxylation

• The equations reflecting these bypass steps include:

  • Fructose 1,6-bisphosphate to Fructose 6-Phosphate:

  • Catalyzed by Fructose 1,6-bisphosphatase - an allosteric enzyme that is regulated in conjunction with PFK.

  • Glucose 6-phosphate to Glucose:

  • Catalyzed by Glucose 6-phosphatase - This step, which generates free glucose, occurs primarily in the liver and marks the final step of gluconeogenesis.

  • Hydrolytic reactions bypass phosphofructokinase and hexokinase.

Energy Considerations

• Both Glycolysis and Gluconeogenesis are spontaneous reactions.

• If both pathways are active simultaneously in a cell, this would create a "futile cycle" wasting energy.

  • Glycolysis Reaction:

  • $ext{glucose} + 2 ext{NAD}^+ + 2 ext{ADP} + 2 ext{Pi} <br>ightarrow 2 ext{pyruvate} + 2 ext{NADH} + 2 ext{ATP}$

  • Gluconeogenesis Reaction:

  • $2 ext{pyruvate} + 2 ext{NADH} + 4 ext{ATP} + 2 ext{GTP} <br>ightarrow ext{glucose} + 2 ext{NAD}^+ + 4 ext{ADP} + 2 ext{GDP} + 6 ext{Pi}$

Energy Yield/Expenditure

• Questions on energy dynamics:

  1. Glycolysis yields how many high-energy phosphate bonds (~P)?

  • Yields: 2

  1. Gluconeogenesis expends how many high-energy phosphate bonds?

  • Expends: 6

  1. Net loss in a futile cycle:

  • Waste: 4 high-energy phosphate bonds per cycle.

Regulation of Glycolysis and Gluconeogenesis

• Reciprocal Regulation

  • Glycolysis and gluconeogenesis are regulated reciprocally, especially at the reaction converting fructose 1,6-bisphosphate to fructose 6-phosphate.

  • Fructose-2,6-bisphosphate allosterically activates phosphofructokinase.

  • Fructose-2,6-bisphosphate allosterically inhibits fructose-1,6-bisphosphatase.

  • Reciprocal regulation also occurs at the interconversion of phosphoenolpyruvate and pyruvate.

• Condition-based Regulation:

  • If ATP is required, glycolysis predominates.

  • If glucose is required, gluconeogenesis is favored.