Ten steps converting glucose to two pyruvate, with a net gain of two ATP
Mnemonic
“Glycolysis costs 2 and makes 4”, giving a net 2 ATP and 2 NADH per glucose:
- Investment phase - 2 ATP consumed, at hexokinase (glucokinase in liver) and phosphofructokinase-1
- Payoff phase - 4 ATP and 2 NADH produced, at phosphoglycerate kinase and pyruvate kinase
Three irreversible steps are the three regulated ones, and they are bypassed by different enzymes in gluconeogenesis:
- Hexokinase / glucokinase
- Phosphofructokinase-1, the rate limiting step, inhibited by ATP and citrate, activated by AMP and fructose-2,6-bisphosphate
- Pyruvate kinase
“PFK-1 is the pacemaker.”
Glycolysis is the only pathway producing ATP without oxygen, which is why mature red cells, which have no mitochondria, depend on it entirely, and why they are vulnerable to pyruvate kinase deficiency.
Expansion
Occurs in the cytoplasm, requires no oxygen, and yields 2 ATP and 2 NADH per glucose.
Three irreversible, regulated steps
- Hexokinase (glucokinase in liver and beta cells): glucose to glucose-6-phosphate. Traps glucose in the cell. Glucokinase has a high Km, so it acts as the liver’s glucose sensor
- Phosphofructokinase-1: the rate-limiting step. Inhibited by ATP and citrate (signals of energy sufficiency), activated by AMP and by fructose-2,6-bisphosphate
- Pyruvate kinase: phosphoenolpyruvate to pyruvate
The investment phase consumes 2 ATP; the payoff phase yields 4, hence the net of 2.
Fate of pyruvate depends on oxygen: aerobically it enters the mitochondrion for the Krebs cycle; anaerobically it becomes lactate, regenerating NAD+ so glycolysis can continue.
Clinical illustrations: pyruvate kinase deficiency causes haemolytic anaemia, since red cells depend entirely on glycolysis; and gluconeogenesis bypasses the three irreversible steps with separate enzymes, which is why the two pathways can be regulated independently.