14 Glycolysis and Gluconeogenesis

Glycolysis and Gluconeogenesis

General Concepts

• Monosaccharide Glucose: A crucial metabolic intermediate in human metabolism.

• Glycolysis: Pathway converting glucose to pyruvate or lactate, core mechanism for energy production.

• Gluconeogenesis: Reverses glycolysis, converting lactate or pyruvate back to glucose.

Major Catabolic Pathways

• Combined pathways of glycolysis and citric acid cycle form the basic energy-yielding mechanisms.

• Various substrates like amino acids and glycerol feed into glycolysis.

• Aerobic Conditions: Glycolysis produces pyruvate, converted to acetyl-CoA and CO2 by pyruvate dehydrogenase, then oxidized in TCA cycle.

Glycolysis Pathway Summary

• Glucose is a primary fuel, rich in potential energy due to reduced carbon.

• Process Phases:

  • Phase 1: Glucose (6 carbons) → 2 Glyceraldehyde-3-phosphate (3 carbons) using 2 ATP.

  • Phase 2: 2 Glyceraldehyde-3-phosphate → 2 Pyruvate generating 4 ATP.

Key Intermediates and Products of Glycolysis

• Glycolysis Steps:

  • Glucose converts into 2 Pyruvate with net output:

    • 2 Pyruvate

    • 2 ATP

    • 2 NADH

Glycolysis Parts

Part I: Top Half of Glycolysis

• Divided for visualization, involves:

  • Five Steps and Enzymes: Converts glucose to G3P.

  • ATP used: 2 ATP equivalents.

  • Final step interconverts DHAP and G3P producing 2 G3P.

Part II: Bottom Half of Glycolysis

• Also consists of five steps mirroring Part I.

• Key Step: G3P to 1,3-bisphosphoglycerate produces NADH, enters oxidative phosphorylation for ATP production.

• ATP Yield:

  • ATP generation occurs at multiple sites, additional 2 ATP produced.

  • Net Yield: 2 ATP and 2 Pyruvate from glycolysis.

Energy Payoff in Glycolysis

• Glyceraldehyde 3-phosphate dehydrogenase introduces phosphate, produces NADH.

• Phosphoglycerate kinase reaction: First ATP production via substrate-level phosphorylation.

Energetics of Glycolysis

Standard Free Energies of Hydrolysis

• Phosphorylation requires energy while dephosphorylation releases energy, ensuring favorable reaction conditions.

Free Energy Changes in Glycolysis and TCA Cycle

• Key points include:

  • Overall negative free energy change for glucose to CO2 is critical for product formation.

  • Slightly uphill reactions must theoretically release energy for pathway continuity.

  • Validity of free energy data affects reaction predictions.

Glycolysis vs Glyconeogenesis

• Glycolysis generates 2 ATP, gluconeogenesis requires 6 ATP.

• Each step in gluconeogenesis corresponds to reversed glycolysis reactions, ensuring ΔG remains negative.

Summary of Aerobic and Anaerobic Glycolysis

• Aerobic Glycolysis: Two pyruvate yield and potential for additional ATP via NADH.

• Anaerobic Glycolysis: Converts pyruvate to lactate to regenerate NAD+ without gaining additional ATP.

The Cori Cycle

• Describes lactate conversion back to glucose post-exercise in liver.

Entry of Other Sugars into Glycolysis

• Sucrose: Converted to glucose and fructose by invertase.

• Fructose Integration: Enters via fructokinase, resulting in glyceraldehyde and dihydroxyacetone phosphate.

• Galactose: Converted to glucose 6-phosphate through a series of reactions involving galactose kinase and UDP-glucose.

Biochemical Regulation of Glycolysis and Gluconeogenesis

• Reciprocal Regulation: Prevents simultaneous operation of pathways.

• Enzyme regulation is essential for controlling metabolic processes under different energy requirements.

Energy Charge Formula

• Measures availability of high-energy phosphates in the cell; governs regulation of glycolysis and gluconeogenesis.

Feedback Mechanisms

• Negative Feedback: High ATP levels inhibit glycolysis.

• Positive Feedback: Low energy charge boosts glycolysis activity.

• Careful regulation ensures metabolic efficiency without wasteful ATP expenditure.