Glycolysis and Gluconeogenesis In-Depth Notes

Glycolysis and Gluconeogenesis Overview

• Glycolysis: Metabolic pathway converting glucose to pyruvate/lactate.
• Gluconeogenesis: Reversal of glycolysis, converting pyruvate/lactate back to glucose.
• Both pathways form core of human metabolism.

Major Catabolic Pathways

• Glycolysis and the citric acid cycle yield energy.
• Carbohydrates, amino acids, and glycerol enter glycolysis.
• Under aerobic conditions, glycolysis produces:
  • Pyruvate
  • AcetylCoA via pyruvate dehydrogenase
  • Carbon dioxide in citric acid cycle.

Glycolysis Summary

• Glucose: Main metabolic fuel, high energy potential.
• Glycolysis phases:
  • Phase 1: Glucose (6C) converted to 2 Glyceraldehyde-3-phosphate (3C), costs 2 ATP.
  • Phase 2: 2 Glyceraldehyde-3-phosphate to 2 Pyruvate, generates 4 ATP.

Key Intermediates and Products of Glycolysis

• Overview of conversion:
  • Glucose to 2 Pyruvate (3C each).
  • 2 ATP used, 4 ATP generated (net gain of 2 ATP).
  • Production of 2 NADH.

Glycolysis Reaction Steps

• Part 1 (Top of pathway):
  • 5 enzymatic steps converting glucose to 2 Glyceraldehyde 3-phosphate.
  • Costs cell 2 ATP equivalents.
• Part 2 (Bottom of pathway):
  • 5 steps, converts Glyceraldehyde 3-phosphate to Pyruvate.
  • Key reactions produce ATP and NADH, leading to regeneration of ATP used earlier.

Energetics of Glycolysis

• Hydrolysable energy of hexoses and trioses:
  • Hexoses (e.g., glucose) require 3 - 5 kcal/mol for phosphorylation.
• Overall free energy change from glucose to carbon dioxide is highly negative.
• Thermodynamics ensures pathways proceed in product formation direction.

Important Enzymatic Reactions

• Hexokinase: Converts glucose to glucose-6-phosphate; keeps glucose from exiting the cell.
• Phosphoglucose Isomerase: Converts glucose-6-phosphate to fructose-6-phosphate.
• Phosphofructokinase: Converts fructose-6-phosphate to fructose-1,6-bisphosphate using ATP.
• Aldolase: Splits a six-carbon compound into two three-carbon compounds.
  • Triose Phosphate Isomerase: Converts dihydroxyacetone phosphate to glyceraldehyde-3-phosphate.

Energy Producing Reactions in Glycolysis

• Glyceraldehyde 3-Phosphate Dehydrogenase: Introduces phosphate and produces NADH, allowing energy capture through ATP generation.
• Phosphoglycerate Kinase and Pyruvate Kinase: Facilitate direct ATP synthesis through substrate-level phosphorylation.

Differences Between Aerobic and Anaerobic Glycolysis

• Aerobic conditions yield:
  • 2 Pyruvate, 2 ATP, 2 NADH (up to 4 more ATP from NADH).
• Anaerobic conditions yield only 2 ATP from glycolysis (lactate production) with no further NADH utilization.

Lactate and Ethanol Fermentation

• Lactate Fermentation: Pyruvate is converted to lactate, regenerating NAD+ from NADH.
• Ethanol Fermentation: Pyruvate converted to acetaldehyde and then to ethanol, also regenerating NAD+.
• Both processes yield 2 ATP; no net production of NADH.

Entry of Alternate Sugars into Glycolysis

• Sucrose: Hydrolyzed to glucose/fructose, entering metabolism through specialized pathways.
• Fructose: Phosphorylated by fructokinase, integrated into glycolysis through aldolase and triose kinase reactions.
• Galactose: Must be converted by a series of reactions before being processed by glycolysis.

Gluconeogenesis Overview

• Converts lactate/pyruvate back to glucose during recovery from exercise.
• Utilizes many glycolytic enzymes; bypass essential irreversible steps with different pathways and enzymes.
• Net cost is 6 ATP equivalents.

Regulatory Aspects of Glycolysis and Gluconeogenesis

• Reciprocal Regulation: Prevents simultaneous high activity in both pathways, emphasizing need-based control (ATP/AMP ratios).
• Key regulation sites involve highly energy-demanding steps with distinct enzymes in both pathways allowing differential regulation.
• Regulation involves allosteric mechanisms responding to cellular energy levels and metabolite signals.
• Fructose-2,6-bisphosphate: Acts positively/negatively on key glycolytic enzymes, illustrating complex metabolic control.

Conclusion

• Glycolysis is crucial for energy production in both aerobic and anaerobic pathways, while gluconeogenesis is vital during recovery and energy storage, regulated tightly to maintain metabolic balance.