Glycolysis

Feature	Aerobic Glycolysis	Anaerobic Glycolysis
Final Product	Pyruvate	Lactate
Net ATP	2 ATP	2 ATP
Net NADH	2 NADH	0 NADH
NAD+ Regeneration	ETC (requires O₂)	Lactate Dehydrogenase
Total ATP/Glucose	~32 ATP (including TCA/OxPhos)	2 ATP
Location	Cytoplasm → Mitochondria	Cytoplasm only
Rate	Slower	Faster

• Pathway Overview
  • Function: Primary pathway for glucose metabolism to produce ATP and intermediates for other pathways.
  • Location: Cytosol of all cells.
  • Oxygen Requirement: Can function aerobically (pyruvate → acetyl-CoA → TCA cycle) or anaerobically (pyruvate → lactate).
  • Phases:
    • Investment Phase: Consumes 2 ATP.
    • Payoff Phase: Generates 4 ATP and 2 NADH.
• Net Products (per 1 glucose molecule)
  • 2 Pyruvate
  • 2 ATP (net)
  • 2 NADH
• Fate of Products:
  • Aerobic Glycolysis
    • Pyruvate: Transported into the mitochondria. Converted to Acetyl-CoA by the Pyruvate Dehydrogenase (PDH) complex.
    • NADH: “Shuttled” into the mitochondria (e.g., malate-aspartate, glycerol-3-phosphate shuttles) to donate electrons to the electron transport chain (ETC).
  • Anaerobic Glycolysis
    • Lactate Dehydrogenase (LDH) converts pyruvate to lactate, oxidizing NADH to NAD+.
    • This regeneration of NAD+ is the critical step, as NAD+ is required for the glyceraldehyde-3-phosphate dehydrogenase step of glycolysis to continue.
• Irreversible/Regulatory Enzymes (High-Yield)
  • 1. Hexokinase / Glucokinase
    • Reaction: Glucose → Glucose-6-Phosphate. Traps glucose inside the cell.
    • Hexokinase: Found in most tissues. ↓ Km (high affinity), ↓ Vmax. Inhibited by its product, Glucose-6-P.
    • Glucokinase: Found in liver & pancreatic β-cells. ↑ Km (low affinity), ↑ Vmax. Functions as a glucose sensor. Induced by insulin. Not inhibited by Glucose-6-P.
  • 2. Phosphofructokinase-1 (PFK-1)
    • Reaction: Fructose-6-P → Fructose-1,6-bisphosphate.
    • This is the main rate-limiting step of glycolysis.
    • Activators:
      • AMP (signals low energy state).
      • Fructose-2,6-bisphosphate (most potent activator).
    • Inhibitors:
      • ATP (signals high energy state).
      • Citrate (signals sufficient TCA cycle intermediates).
  • 3. Pyruvate Kinase
    • Reaction: Phosphoenolpyruvate (PEP) → Pyruvate. Generates ATP via substrate-level phosphorylation.
    • Activators:
      • Fructose-1,6-bisphosphate (feed-forward activation).
    • Inhibitors:
      • ATP
      • Alanine
• Regulation of Fructose-2,6-bisphosphate (F-2,6-BP)
  • Controls the switch between glycolysis and gluconeogenesis.
  • Synthesized/degraded by a bifunctional enzyme (PFK-2/FBPase-2).
  • Fed State (↑ Insulin): Dephosphorylation of PFK-2/FBPase-2. PFK-2 domain is active → ↑ F-2,6-BP → ↑ PFK-1 activity → Glycolysis favored.
  • Fasting State (↑ Glucagon): Phosphorylation of PFK-2/FBPase-2 via PKA. FBPase-2 domain is active → ↓ F-2,6-BP → ↓ PFK-1 activity → Gluconeogenesis favored.
• Clinical Correlations
  • Pyruvate Kinase Deficiency
    • Autosomal recessive disorder.
    • Causes ↓ ATP production in RBCs → membrane failure → extravascular hemolytic anemia.
    • RBCs swell and are cleared by the spleen (splenomegaly).
    • Findings: Burr cells (echinocytes) on peripheral smear.
  • Arsenic Poisoning
    • Inhibits enzymes requiring lipoic acid, primarily the pyruvate dehydrogenase complex (PDH), blocking entry of pyruvate into the TCA cycle.
    • Also inhibits glyceraldehyde-3-phosphate dehydrogenase, preventing ATP production in glycolysis without stopping the pathway (produces 0 net ATP).
  • Lactic Acidosis
    • Occurs in states of tissue hypoxia (e.g., ischemia, shock) where pyruvate is shunted to lactate via lactate dehydrogenase (LDH) to regenerate NAD+ for continued glycolysis.