Glycolysis is the first step in cellular respiration, breaking down glucose into pyruvate. This process occurs in the cytosol and doesn't require oxygen, making it crucial for energy production in various conditions.

Pyruvate's fate depends on oxygen availability. In aerobic conditions, it enters the citric acid cycle. In anaerobic conditions, it undergoes fermentation. Understanding these pathways is key to grasping cellular energy production.

Glycolysis and Pyruvate Oxidation

Steps and enzymes of glycolysis

• Glycolysis breaks down glucose into pyruvate through a 10-step process (cytosol, anaerobic)
• Key steps and enzymes:
  1. Hexokinase phosphorylates glucose to glucose-6-phosphate (G6P)
  2. Phosphoglucose isomerase converts G6P to fructose-6-phosphate (F6P)
  3. Phosphofructokinase phosphorylates F6P to fructose-1,6-bisphosphate (F1,6BP) (irreversible, rate-limiting)
  4. Aldolase cleaves F1,6BP into glyceraldehyde-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP)
  5. Triose phosphate isomerase converts DHAP to G3P
  6. Glyceraldehyde-3-phosphate dehydrogenase oxidizes G3P to 1,3-bisphosphoglycerate (1,3BPG), reduces NAD+ to NADH
  7. Phosphoglycerate kinase converts 1,3BPG to 3-phosphoglycerate (3PG), produces ATP (substrate-level phosphorylation)
  8. Phosphoglycerate mutase converts 3PG to 2-phosphoglycerate (2PG)
  9. Enolase dehydrates 2PG to phosphoenolpyruvate (PEP)
  10. Pyruvate kinase converts PEP to pyruvate, produces ATP (substrate-level phosphorylation)

Glucose to pyruvate conversion

• Glycolysis converts one glucose molecule into two pyruvate molecules
• Energy yield per glucose molecule:
  • Net production of 2 ATP via substrate-level phosphorylation (4 ATP produced, 2 ATP consumed)
  • Net production of 2 NADH (used in electron transport chain for ATP generation)
• Redox reactions involve NAD+ reduction to NADH by glyceraldehyde-3-phosphate dehydrogenase
• Phosphorylation events occur twice through substrate-level phosphorylation (phosphoglycerate kinase and pyruvate kinase steps)

Pyruvate fate in aerobic vs anaerobic conditions

• Aerobic conditions (oxygen available):
  • Pyruvate converted to acetyl-CoA by pyruvate dehydrogenase complex, enters citric acid cycle
  • NADH from glycolysis used in electron transport chain for ATP generation
• Anaerobic conditions (oxygen unavailable):
  • Fermentation regenerates NAD+ for glycolysis continuation
  • Lactic acid fermentation (animals, some microorganisms): pyruvate reduced to lactate by lactate dehydrogenase, NADH oxidized to NAD+
  • Alcoholic fermentation (yeast, some microorganisms): pyruvate decarboxylated to acetaldehyde by pyruvate decarboxylase, acetaldehyde reduced to ethanol by alcohol dehydrogenase, NADH oxidized to NAD+

Pyruvate dehydrogenase complex role

• Pyruvate dehydrogenase complex (PDC) is a multi-enzyme complex in the mitochondrial matrix
• Catalyzes irreversible oxidative decarboxylation of pyruvate to acetyl-CoA, committing pyruvate to citric acid cycle
• Reaction: $Pyruvate + CoA + NAD^+ \rightarrow Acetyl-CoA + CO_2 + NADH$
• PDC regulation:
  • Allosteric inhibition by high acetyl-CoA and NADH levels
  • Covalent modification (phosphorylation) by pyruvate dehydrogenase kinase inactivates PDC
  • Dephosphorylation by pyruvate dehydrogenase phosphatase activates PDC
• Acetyl-CoA produced by PDC enters citric acid cycle, generating NADH and FADH2 for electron transport chain and ATP production through oxidative phosphorylation