Methylmalonyl CoA epimerase

methylmalonyl CoA epimerase

Ribbon diagram of methylmalonyl-CoA epimerase from Propionibacterium shermanii. From PDB: 1JC5.
EC number
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
methylmalonyl CoA epimerase
Symbol MCEE
Entrez 84693
HUGO 16732
OMIM 608419
RefSeq NM_028626
UniProt Q96PE7
Other data
EC number
Locus Chr. 2 p13.3

Methylmalonyl CoA epimerase (EC, methylmalonyl-CoA racemase, methylmalonyl coenzyme A racemase, DL-methylmalonyl-CoA racemase, 2-methyl-3-oxopropanoyl-CoA 2-epimerase [incorrect]) is an enzyme involved in fatty acid catabolism that is encoded in human by the "MCEE" gene located on chromosome 2.


The "MCEE" gene is located in the 2p13 region and contains 4 exons, and encodes for a protein that is approximately 18 kDa in size and located to the mitochondrial matrix.[1] Several natural variants in amino acid sequences exist. The structure of the MCEE protein has been resolved by X-ray crystallography [2] at 1.8-angstrom resolution.


The MCEE gene encodes an enzyme that interconverts D- and L- methylmalonyl-CoA during the degradation of branched-chain amino acids, odd chain-length fatty acids, and other metabolites. In biochemistry terms, it catalyzes the reaction that converts (S)-methylmalonyl-CoA to the (R) form.[3][4] This enzyme catalyses the following chemical reaction

(R)-methylmalonyl-CoA (S)-methylmalonyl-CoA

Methylmalonyl CoA epimerase plays an important role in the catabolism of fatty acids with odd-length carbon chains. In the catabolism of even-chain saturated fatty acids, the β-oxidation pathway breaks down fatty acyl-CoA molecules in repeated sequences of four reactions to yield one acetyl CoA per repeated sequence. This means that, for each round of β-oxidation, the fatty acyl-Co-A is shortened by two carbons. If the fatty acid began with an even number of carbons, this process could break down an entire saturated fatty acid into acetyl-CoA units. If the fatty acid began with an odd number of carbons, however, β-oxidation would break the fatty acyl-CoA down until the three carbon propionyl-CoA is formed. In order to convert this to the metabolically useful succinyl-CoA, three reactions are needed. The propionyl-CoA is first carboxylated to (S)-methylmalonyl-CoA by the enzyme Propionyl-CoA carboxylase. Methylmalonyl CoA epimerase then catalyzes the rearrangement of (S)-methylmalonyl-CoA to the (R) form in a reaction that uses a vitamin B12 cofactor and a resonance-stabilized carbanion intermediate. The (R)-methylmalonyl-CoA is then converted to succinyl-CoA in a reaction catalyzed by methylmalonyl-CoA mutase.

Acting as a general base, the enzyme abstracts a proton from the β-carbon of (R)-methylmalonyl-CoA. This results in the formation of a carbanion intermediate in which the α-carbon is stabilized by resonance. The enzyme then acts as a general acid to protonate the β-carbon, resulting in the formation of (S)-methylmalonyl-CoA.

Clinical Significance

Mutations in the MCEE gene causes Methymalonyl-Coa epimerase deficiency (MCEED),[5] a rare autosomal recessive inborn error of metabolism in amino acid metabolisms involving branched-chain amino acids valine, threonine, isoleucine, and methionine. Patients with MCEED may present with life-threatening neonatal metabolic acidosis, hyperammonemia, feeding difficulties, and coma.


  3. Mazumder, R.; Sasakawa, T.; Kaziro, Y.; Ochoa, S. (1962). "Metabolism of propionic acid in animal tissues. IX. Methylmalonyl coenzyme A racemase". J. Biol. Chem. 237: 3065–3068. PMID 13934211.
  4. Overath, P.; Kellerman, G.M.; Lynen, F.; Fritz, H.P.; Keller, H.J. (1962). "Zum Mechanismus der Umlagerung von Methylmalonyl-CoA in Succinyl-CoA. II. Versuche zur Wirkungsweise von Methylmalonyl-CoA-Isomerase and Methylmalonyl-CoA-Racemase". Biochem. Z. 335: 500–518. PMID 14482843.
  5. Bikker H, Bakker HD, Abeling NG, Poll-The BT, Kleijer WJ, Rosenblatt DS, Waterham HR, Wanders RJ, Duran M (2006). "A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria". Hum. Mutat. 27 (7): 640–3. doi:10.1002/humu.20373. PMID 16752391.
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