LSC10064 Gluconeogenesis 2024

Introduction to Gluconeogenesis

• Gluconeogenesis is the metabolic pathway through which glucose is synthesized from non-carbohydrate precursors.

• The process occurs mainly in the liver and is crucial when glycogen stores are depleted.

• Gluconeogenesis is not merely the reversal of glycolysis due to the presence of irreversible steps.

Lecture Outcomes

• Understand key components of gluconeogenesis:

  • Name the compounds and intermediates involved.

  • Draw their structures.

  • List enzymatic reactions and identify the enzymes involved.

  • Understand control points and regulatory molecules (activators/inhibitors).

Gluconeogenesis Overview

• The body converts non-glucose precursors into glucose, particularly when glycogen is low.

• Cori Cycle:

  • An important inter-tissue reaction cycle that recycles lactate back to glucose.

  • High levels of lactate from muscle activity shift metabolic burden to the liver for conversion to glucose.

Cori Cycle

• Process:

  • In muscle, lactate is produced from pyruvate.

  • In the liver, lactate is converted back to pyruvate and then to glucose through gluconeogenesis.

Glycolysis Overview

• Glycolysis consists of three stages involved in the breakdown of glucose:

  1. Stage 1: Energy investment phase requiring ATP.

  2. Stage 2: Splitting glucose into two three-carbon molecules.

  3. Stage 3: Energy generation by producing ATP and NADH.

Stages of Glycolysis - Detailed Steps

Stage 1: Energy Investment

• Key Enzymes:

  • Hexokinase: Converts glucose to glucose-6-phosphate, consuming ATP.

  • Phosphofructokinase: Converts fructose-6-phosphate to fructose-1,6-bisphosphate, the main regulatory step.

Stage 2: Cleavage and Rearrangement

• Enzymes involved:

  • Aldolase: Cleaves fructose-1,6-bisphosphate into dihydroxyacetone phosphate and glyceraldehyde-3-phosphate.

  • Isomerase: Converts between DHAP and GAP.

Stage 3: ATP Generation

• Produces ATP via substrate-level phosphorylation.

• Key Enzymes Include:

  • Glyceraldehyde-3-phosphate dehydrogenase (produces NADH).

  • Phosphoglycerate kinase (produces ATP).

  • Pyruvate kinase (final step producing pyruvate and generating ATP).

Key Features of Glycolytic Reactions

• Each enzymatic reaction has an associated Gibbs free energy change (ΔG).

• Notable Energetic Changes:

  • Hexokinase reaction: highly exergonic (-33.5 kJ/mol).

  • Pyruvate kinase reaction: also highly exergonic, critical for driving glycolysis forward.

Comparison of Glycolysis and Gluconeogenesis

• Gluconeogenesis is more energy costly than glycolysis.

• Requires bypass reactions for irreversible steps in glycolysis.

• Process Involves:

  • Pyruvate carboxylase and phosphoenolpyruvate carboxykinase for converting pyruvate to phosphoenolpyruvate.

  • Fructose-1,6-bisphosphatase for converting fructose-1,6-bisphosphate to fructose-6-phosphate.

Regulation of Gluconeogenesis

• Influenced by several metabolites and energy levels:

  • High ATP levels stimulate gluconeogenesis.

  • Fructose-2,6-bisphosphate and AMP inhibit gluconeogenesis.

Pathways Interlinkage

• Tissues Involved:

  • Primarily occurs in liver and kidney with contributions from muscle and red blood cells.

  • Integration of substrates from lactate, pyruvate, and amino acids into gluconeogenesis.

Summary of Key Points

• Reversible vs. Irreversible Steps: Gluconeogenesis bypasses three key irreversible steps in glycolysis.

• Energetics: Gluconeogenesis is energetically costlier than glycolysis but is essential for maintaining glucose levels during fasting.

• Understanding the interconnected pathways facilitates a deeper comprehension of metabolic regulation.