Acetyl-CoA
High-Yield Summary
- Acetyl-CoA — not glucose or pyruvate — is the molecule that enters the citric acid cycle. It's also the starting material for fatty acid, cholesterol, and ketone body synthesis.
- Pyruvate dehydrogenase complex (PDC) converts pyruvate → acetyl-CoA via oxidative decarboxylation in the mitochondrial matrix: 1 pyruvate → 1 acetyl-CoA + 1 NADH + 1 CO2. Irreversible — carbon can't go back to glucose from here.
- PDC has 3 catalytic enzymes (using TPP, lipoic acid + CoA, and FAD + NAD⁺) and 2 regulatory enzymes: PDC kinase (off switch, activated by acetyl-CoA/NADH) and PDC phosphatase (on switch, stimulated by insulin and calcium).
- Four other acetyl-CoA sources beyond glucose: fatty acid beta-oxidation (via the carnitine shuttle), ketogenic amino acids, ketone bodies (in peripheral tissues), and alcohol metabolism.
Key Terms
- Oxidative decarboxylation
- Reaction removing a carbon as CO2 while oxidizing the remaining fragment — how PDC converts pyruvate to acetyl-CoA.
- Lipoic acid
- Cofactor that acts as a flexible arm, swinging the acetyl group between PDC active sites.
- Carnitine shuttle
- Transports fatty acyl groups across the inner mitochondrial membrane by swapping between CoA and carnitine.
- PDC kinase / PDC phosphatase
- Regulatory enzymes that phosphorylate (inactivate) / dephosphorylate (activate) PDC.
PDC's Three Catalytic Enzymes
| Enzyme | Cofactor / Job |
|---|---|
| Pyruvate dehydrogenase | TPP — removes 1 carbon from pyruvate as CO2 |
| Dihydrolipoyl transacetylase | Lipoic acid + CoA — transfers acetyl group onto CoA |
| Dihydrolipoyl dehydrogenase | FAD + NAD⁺ — reoxidizes lipoic acid, produces NADH |
PDC Regulation
| Regulator | Effect |
|---|---|
| PDC kinase (off switch) | Activated by acetyl-CoA, NADH; inhibited by pyruvate, CoA, NAD⁺, ADP |
| PDC phosphatase (on switch) | Stimulated by insulin (fed state) and calcium (muscle activity) |
Other Sources of Acetyl-CoA
- 1Fatty acid beta-oxidation: fatty acyl-CoA formed in cytosol → carnitine shuttle into matrix → beta-oxidation removes 2-carbon units as acetyl-CoA
- 2Ketogenic amino acids: deamination → carbon skeleton → acetyl-CoA or ketone bodies (cannot support gluconeogenesis)
- 3Ketone bodies: made in liver when acetyl-CoA is high/carbs low → travel to peripheral tissues → reconverted to acetyl-CoA
- 4Alcohol metabolism: ethanol → acetaldehyde → acetate → acetyl-CoA (but generates excess NADH, inhibiting the citric acid cycle and favoring fat accumulation)
Common MCAT Trap
- The citric acid cycle takes in acetyl-CoA, not pyruvate or glucose directly — a common substitution error under time pressure.
- PDC is irreversible — fat (via acetyl-CoA) and ketogenic amino acids can never be converted back into glucose.
- Chronic alcohol use causes fatty liver not because acetyl-CoA production stops, but because excess NADH blocks its oxidation through the citric acid cycle, shunting it toward fat synthesis.
Quick Recall
What three products come from one pyruvate passing through PDC?
What activates PDC kinase (turning PDC off)?
Why can't ketogenic amino acids support gluconeogenesis?