Acetyl-CoA is oxidised, generating NADH, FADH2 and GTP
Mnemonic
“Citrate Is Krebs’ Starting Substrate For Making Oxaloacetate”:
- C - Citrate
- I - Isocitrate
- K - alpha-Ketoglutarate
- S - Succinyl-CoA
- S - Succinate
- F - Fumarate
- M - Malate
- O - Oxaloacetate
Per turn: 3 NADH, 1 FADH2, 1 GTP, 2 CO2. The two oxidative decarboxylations that release the carbon dioxide are isocitrate to alpha-ketoglutarate and alpha-ketoglutarate to succinyl-CoA, and both are irreversible regulatory steps.
The only step producing FADH2 is succinate to fumarate, catalysed by succinate dehydrogenase, which is the only enzyme of the cycle embedded in the inner mitochondrial membrane and is also complex II of the electron transport chain.
Expansion
Occurs in the mitochondrial matrix. Each turn oxidises one acetyl-CoA and yields:
- 3 NADH
- 1 FADH2
- 1 GTP (equivalent to ATP)
- 2 carbon dioxide
Two turns per glucose, since glycolysis produces two pyruvate.
The cycle is the central hub of metabolism: carbohydrate, fat and protein all converge on acetyl-CoA or on cycle intermediates, and intermediates are also drawn off for biosynthesis (cataplerosis) and replenished (anaplerosis), principally by pyruvate carboxylase forming oxaloacetate.
Two conceptually important points:
- Acetyl-CoA cannot be converted to glucose in humans, because the two carbons are lost as carbon dioxide. This is why fatty acids cannot be used for gluconeogenesis, and why fasting still requires protein breakdown. The glycerol backbone of triglyceride is the exception
- Oxaloacetate depletion in starvation and uncontrolled diabetes, as it is diverted to gluconeogenesis, means acetyl-CoA cannot enter the cycle and is instead converted to ketone bodies