Step by Step
PDC
Pyruvate Dehydrogenase Complex (PDC)
The PDC is a large multienzyme complex in the mitochondrial matrix. It catalyzes: Pyruvate (3C) + CoA + NAD⁺ → Acetyl-CoA (2C) + CO₂ + NADH. This is an oxidative decarboxylation — a carbon is lost as CO₂ and the remaining 2C are attached to CoA. Requires 5 cofactors: TPP (B1), lipoic acid, CoA (B5), FAD (B2), NAD⁺ (B3).
Memory trick: 'The Last Can' = TPP, Lipoic acid, CoA, FAD, NAD⁺. All five vitamins involved.
Irr
Irreversible — one-way reaction
Pyruvate oxidation is IRREVERSIBLE — acetyl-CoA cannot be converted back to pyruvate in animals. This means: fatty acids (which enter as acetyl-CoA) CANNOT be converted to glucose. This is why fat cannot make net glucose — the carbons are trapped as acetyl-CoA and are fully oxidized in the TCA cycle.
Memory trick: Once pyruvate becomes acetyl-CoA, it's committed — no going back to glucose.
Reg
Regulation of PDC
PDC is regulated by phosphorylation: PDK (pyruvate dehydrogenase kinase) phosphorylates → INACTIVATES PDC. PDP (phosphatase) dephosphorylates → ACTIVATES PDC. PDK is activated by high NADH, acetyl-CoA, ATP (energy surplus → turn off PDC). PDK is inhibited by high pyruvate, ADP, CoA (need energy → turn on PDC).
Def
PDC deficiency
PDC deficiency (genetic) → pyruvate cannot enter TCA cycle → accumulates → converted to lactate → lactic acidosis. Treatment: ketogenic diet (bypasses PDC by using fat → ketones for brain energy). Thiamine (B1/TPP) deficiency → same consequence → Wernicke's encephalopathy.
Applied Walkthrough
1
After a meal, blood glucose rises → glycolysis produces pyruvate → pyruvate crosses into mitochondrial matrix.
2
PDC converts pyruvate → acetyl-CoA + CO₂ + NADH. Two pyruvates per glucose = 2 acetyl-CoA + 2 CO₂ + 2 NADH.
3
Acetyl-CoA enters the Krebs cycle. This step is the irreversible commitment — the 2 carbons from glucose are now on their way to being fully oxidized to CO₂.
4
In PDC deficiency: pyruvate backs up → lactate accumulates (lactic acidosis). The brain starves for acetyl-CoA unless ketones are supplied.
Exam Application
Exams test the reaction (pyruvate → acetyl-CoA + CO₂ + NADH), location (mitochondrial matrix), irreversibility (fat cannot make glucose), the 5 cofactors (especially B1/TPP), and PDC regulation by phosphorylation. The clinical connection to B1 deficiency (Wernicke's) and PDC deficiency (lactic acidosis) are high yield.
⚠ Common Trap
Students think fatty acids can be converted to glucose via acetyl-CoA — they CANNOT. The pyruvate oxidation step is irreversible. Acetyl-CoA has no way back to pyruvate in animals. Odd-chain fatty acids are the exception (propionyl-CoA → succinyl-CoA → TCA → OAA → GNG) but even-chain fatty acids cannot make net glucose.
✓ Quick Self-Check
1. What does pyruvate oxidation produce?
Acetyl-CoA + CO₂ + NADH (per pyruvate). Per glucose: 2 acetyl-CoA + 2 CO₂ + 2 NADH.
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2. Where does pyruvate oxidation occur?
In the mitochondrial matrix — requires the pyruvate dehydrogenase complex (PDC).
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3. Why can't fatty acids make net glucose?
Fatty acids are converted to acetyl-CoA, and pyruvate oxidation is IRREVERSIBLE — acetyl-CoA cannot be converted back to pyruvate or glucose in animals.
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4. How is PDC regulated?
Phosphorylation inactivates PDC (by PDK); dephosphorylation activates it (by PDP). High NADH/ATP/acetyl-CoA activate PDK (shut off PDC); high pyruvate/ADP/CoA inhibit PDK (turn on PDC).
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5. What vitamin deficiency impairs PDC function?
Thiamine (vitamin B1) — TPP is an essential cofactor for PDC. Deficiency causes Wernicke's encephalopathy.
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