Biochemistry · Metabolic pathway

Propionyl-CoA to succinyl-CoA !

Odd-chain fatty acids and four amino acids leave propionyl-CoA. Three enzymes turn it into succinyl-CoA, which enters the Krebs cycle.

Updated 2026-11-01

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Balance: ATP -1CO₂ -1

Propionyl-CoA comes from valine, odd-chain fatty acids, methionine, isoleucine and threonine (mnemonic VOMIT) and from the cholesterol side chain.
Propionyl-CoA carboxylase needs biotin and ATP and makes D-methylmalonyl-CoA.
Methylmalonyl-CoA mutase needs adenosylcobalamin (B12); it is one of only two human B12 enzymes, with methionine synthase.
Succinyl-CoA feeds the Krebs cycle and can become glucose: this is why the last three carbons of odd-chain fatty acids are glucogenic.
B12 deficiency raises methylmalonic acid; folate deficiency does not.

Flux follows supply: protein intake, fasting and gut bacteria, which make propionate, increase it.
No major allosteric control is known; activity depends on biotin and B12 status.

Step 1 · Propionyl-CoA carboxylase (PCC) irreversible Propionyl-CoA + CO₂ + ATP → D-Methylmalonyl-CoA + ADP + phosphate (Pi)Adds CO₂ (as bicarbonate) to propionyl-CoA using biotin and ATP, making D-methylmalonyl-CoA.If it fails: PCC deficiency (PCCA or PCCB genes): propionic acidaemia with ketoacidosis and hyperammonaemia in the newborn. Propionic acidaemia →
Step 2 · Methylmalonyl-CoA epimerase (MCEE) D-Methylmalonyl-CoA ⇌ L-Methylmalonyl-CoATurns the D form into the L form, the only one the mutase can use.If it fails: MCEE deficiency is rare and usually mild, with a modest rise of methylmalonic acid.
Step 3 · Methylmalonyl-CoA mutase (MMUT), B12-dependent L-Methylmalonyl-CoA ⇌ succinyl-CoAMoves the CoA-carbonyl group inside the molecule by a radical reaction of adenosylcobalamin, giving succinyl-CoA.If it fails: Mutase defects or faults in B12 processing cause methylmalonic acidaemia; dietary B12 deficiency raises methylmalonic acid less dramatically. Methylmalonic acidaemia →

Propionic acidaemia (PCC deficiency): neonatal ketoacidosis, hyperammonaemia and high propionylcarnitine (C3) on newborn screening.
Methylmalonic acidaemia (mutase or B12-cofactor defects): similar crises plus kidney damage; some forms respond to B12.
In B12 deficiency methylmalonic acid is a sensitive test; part of the nerve damage is blamed on abnormal fatty acids made from methylmalonyl-CoA.
Excess propionyl-CoA inhibits N-acetylglutamate synthase, which is why ammonia rises in these disorders.

Think of the answer, then tap the question to see it.

Which vitamins do the first and last steps need?

Biotin for propionyl-CoA carboxylase and adenosylcobalamin (B12) for methylmalonyl-CoA mutase.

Why does methylmalonic acid rise in B12 deficiency but not in folate deficiency?

Methylmalonyl-CoA mutase needs B12, not folate; homocysteine, in contrast, rises in both deficiencies.

Which sources feed propionyl-CoA?

Valine, isoleucine, methionine and threonine, odd-chain fatty acids and the cholesterol side chain.

Why do propionic and methylmalonic acidaemias cause hyperammonaemia?

Propionyl-CoA inhibits N-acetylglutamate synthase, so CPS-I, the first urea cycle enzyme, loses its activator.

Educational information, not medical advice. For any symptom, see a health professional.

Sources: Methylmalonic acidemia: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Propionic acidemia: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); MMUT gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); MCEE gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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Representative model, for educational purposes only.