GLYCOLYSIS

Glycolysis

Overview of Catabolism

  • Catabolism: The breakdown of complex molecules to release energy. Organized into three stages:

    • Stage 1: Digestion - Breakdown of large molecules to smaller ones that can enter the bloodstream.

    • Stage 2: Absorption - Nutrients are absorbed into the cells.

    • Stage 3: Utilization - Cells utilize the absorbed nutrients.

    • Stage 4: Pathway reactions - Involves metabolic pathways.

Structure and Function of Glycolysis

  • Definition: Glycolysis is the oxidation of six-carbon glucose molecules to three-carbon pyruvate molecules in the presence of oxygen or lactate in the absence of oxygen.

  • Developed from Greek roots: "glykys" (sweet) and "lysis" (splitting).

Location of Glycolysis

  1. Intracellular location: Takes place in the cytosol.

  2. Organ location: Occurs in all tissue cells.

  3. Physiological condition: Primarily active after meals.

Types of Glycolysis

  • Aerobic Glycolysis: Requires oxygen to re-oxidize NADH back to NAD+ via the electron transport chain.

  • Anaerobic Glycolysis: NADH is re-oxidized to NAD+ by reducing pyruvate to lactate (in humans) or ethanol (in yeast and other microorganisms).

Steps of Glycolysis

  • Preparation Phase:

    1. Hexokinase Reaction:

    • Reaction: Glucose + ATP → Glucose-6-phosphate + ADP

    1. Phosphoglucose Isomerase Reaction: Glucose-6-phosphate ↔ Fructose-6-phosphate

    2. Phosphofructokinase-1 Reaction:

    • Reaction: Fructose-6-phosphate + ATP → Fructose 1,6-bisphosphate + ADP

Payoff Phase:

  1. Aldolase Reaction:

    • Breaks Fructose 1,6-bisphosphate into Glyceraldehyde-3-phosphate and Dihydroxyacetone phosphate.

  2. Glyceraldehyde-3-phosphate Dehydrogenase Reaction:

    • Conversion: Glyceraldehyde-3-phosphate + NAD+ ↔ 1,3-bisphosphoglycerate + NADH + H+

  3. Phosphoglycerate Kinase Reaction:

    • 1,3-bisphosphoglycerate + ADP → 3-phosphoglycerate + ATP.

  4. Phosphoglycerate Mutase Reaction:

    • 3-phosphoglycerate ↔ 2-phosphoglycerate

  5. Enolase Reaction:

    • 2-phosphoglycerate → Phosphoenolpyruvate + H2O.

  6. Pyruvate Kinase Reaction:

    • Phosphoenolpyruvate + ADP → Pyruvate + ATP.

Energy Yield in Glycolysis

  • Net Gain:

    • From 1 molecule of glucose:

      • Aerobic Glycolysis: 6 ATP (4 ATP from substrate level phosphorylation, plus 2 ATP from NADH oxidation in mitochondria).

      • Anaerobic Glycolysis: 2 ATP (4 ATP - 2 ATP used for initial reactions).

Enzymatic Regulation of Glycolysis

  1. Hexokinase

    • Regulation: Inhibited by glucose-6-phosphate.

    • Affinity: Low Km = 0.1 mM (high affinity for glucose).

  2. Phosphofructokinase (PFK-1)

    • Regulation: Activated by high levels of AMP and inhibited by ATP.

    • Key Control Point: Rate-limiting step of glycolysis.

  3. Pyruvate Kinase (PK)

    • Regulation: Inhibited by ATP and acetyl CoA.

    • Function: Catalyzes the final step of glycolysis.

Hormonal Regulation of Glycolysis

  • Insulin stimulates glycolysis in liver, enhances fructose 2,6-bisphosphate levels which activates PFK-1.

  • Glucagon counteracts insulin effects during fasting, inhibits glycolysis and promotes gluconeogenesis.

Clinical Significance of Glycolysis

  • Diseases associated with impaired glycolysis:

    1. Pyruvate Kinase Deficiency: Reduction in ATP production leads to hemolytic anemia due to unstable RBCs.

    2. Hexokinase Deficiency: Low ATP production, also causes hemolytic anemia.

    3. Lactic Acidosis: Increased blood lactate causes metabolic acidosis, potentially leading to coma.

Causes of Lactic Acidosis

  1. Excessive anaerobic exercise.

  2. Use of certain oral hypoglycemic drugs.

Anaerobic Glycolysis and Fermentation

  • Fermentation: Process where pyruvate is converted to ethanol (in yeast) or lactate (in humans) under anaerobic conditions to regenerate NAD+

Consequences of Lactic Acid Accumulation

  • Muscle pain post-exercise.

  • Increased risk of lactic acidosis.

  • Potentially lethal conditions like myocardial infarction (heart attack).

Glycolytic Pathway Intermediates and Importance

  • Provides essential intermediates for biosynthetic pathways:

    • Dihydroxyacetone phosphate: Synthesis of triglycerides and phospholipids.

    • 3-Phosphoglycerate: Can be converted into the amino acid serine.

    • Pyruvate: Can be converted into the amino acid alanine.

Summary of Glycolysis

  • Glycolysis is crucial for energy production, especially in tissues lacking oxygen (e.g., erythrocytes and muscles) and in the brain, which relies heavily on glucose for energy.

  • It plays a significant role in metabolic processes and provides essential compounds for various biosynthetic pathways.

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