STEPTRACKERBIOCHEMISTRY + TOXICOLOGY | CARBOHYDRATE METABOLISM | HIGH-YIELD REVIEW

Pyruvate Fates & PDH

Pyruvate has four exits; the PDH complex is the gate into the TCA cycle and needs five cofactors — lose one and lactate piles up.

FOCUS ON
Four fates: alanine (ALT, B6) → carry amino groups to liver; oxaloacetate (pyruvate carboxylase, biotin) → gluconeogenesis/TCA; acetyl-CoA (PDH) → TCA; lactate (LDH) → regenerates NAD⁺. PDH cofactors: B1 (TPP), lipoic acid, B2 (FAD), B3 (NAD⁺), B5 (CoA). PDH deficiency → lactic acidosis, neuro problems; treat with ketogenic diet (lysine, leucine). Arsenite blocks lipoic acid.
FATE · TOPIC
ENZYME · COFACTOR
PURPOSE
CLUE
→ Alanine
ALT (alanine aminotransferase) · B6
Carries nitrogen from muscle to liver (Cahill cycle)
Alanine → pyruvate → glucose in liver
→ Oxaloacetate
Pyruvate carboxylase (mitochondria) · biotin, ATP; activated by acetyl-CoA
Replenishes TCA intermediates; first step of gluconeogenesis
Biotin deficiency → lactic acidosis
→ Acetyl-CoA
Pyruvate dehydrogenase complex (mitochondria) · TPP, lipoate, CoA, FAD, NAD⁺
Enters TCA cycle; fatty acid synthesis
Irreversible — acetyl-CoA can't make net glucose
→ Lactate
Lactate dehydrogenase · NADH
Regenerates NAD⁺ for glycolysis; Cori cycle
RBCs, exercise, hypoxia, shock
PDH activation
Dephosphorylated (active) by PDH phosphatase
↑ NAD⁺/NADH, ↑ ADP, ↑ Ca²⁺ (exercising muscle), insulin
—
PDH inhibition
Phosphorylated by PDH kinase
↑ Acetyl-CoA, ↑ NADH, ↑ ATP (products)
Fasting favors fat use, spares pyruvate for glucose
α-Ketoglutarate dehydrogenase
Same five cofactors as PDH
TCA step (8.03)
Also blocked in thiamine deficiency and by arsenite
PDH deficiency
usually X-linked (E1α)
Pyruvate → alanine and lactate
Neurologic defects, lactic acidosis, ↑ serum alanine, from infancy
↑ ketogenic nutrients: lysine and leucine (purely ketogenic amino acids), high fat
Arsenic poisoning
Arsenite binds lipoic acid → PDH, α-KG DH blocked
Vomiting, rice-water stools, garlic breath, QT prolongation, Mees lines
Chelate with dimercaprol / succimer
Cori cycle
Muscle/RBC lactate → liver → glucose → back
Costs the liver 4 ATP net per cycle (6 used, 2 made)
Glucose-alanine cycle is the nitrogen-carrying version

Mechanism — four exits for pyruvate

Pyruvate
→
ALT (B6)Alanine
Pyruvate carboxylase (biotin)Oxaloacetate
PDH (B1, lipoate, B2, B3, B5)Acetyl-CoA
LDH (NADH)Lactate

Fed: PDH on, pyruvate → acetyl-CoA. Fasting: acetyl-CoA from fat turns PDH off and pyruvate carboxylase on → glucose.

Thiamine-dependent enzymes

ENZYME
PATHWAY
BLOCK CAUSES
PDH
Glycolysis → TCA
Lactic acidosis
α-KG DH
TCA
↓ ATP
Transketolase
HMP shunt
↓ Ribose/NADPH balance
BCKDH
Branched-chain AA
MSUD-like

How it's tested

COMMON CONFUSIONLysine and leucine are the only purely ketogenic amino acids — they bypass PDH, which is why they help in PDH deficiency.
THE TRAPGarlic breath + GI symptoms + lactic acidosis → arsenic (lipoic acid), not thiamine deficiency.
YOUR APPROACHLactic acidosis with normal oxygenation → ask which pyruvate exit is blocked (PDH, cofactor, poison, mitochondria).

If you see… think…

Infant with lactic acidosis and ↑ alanine → PDH deficiency
Dietary treatment for PDH deficiency → ketogenic: lysine, leucine, fat
PDH cofactors → TPP, lipoic acid, CoA, FAD, NAD⁺
Garlic breath, vomiting, lactic acidosis → arsenic (lipoic acid)
Enzyme activated by acetyl-CoA for gluconeogenesis → pyruvate carboxylase
Cofactor of pyruvate carboxylase → biotin
Nitrogen shuttle from muscle to liver → alanine (glucose-alanine cycle)
Lactate from muscle recycled to glucose → Cori cycle
PDH turned off by → its products: acetyl-CoA, NADH, ATP
Exercise activates PDH in muscle via → Ca²⁺, ADP