Methylmalonyl CoA epimerase

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methylmalonyl CoA epimerase
Methylmalonyl-CoA epimerase 1JC5.png
Ribbon diagram of methylmalonyl-CoA epimerase from Propionibacterium shermanii. From PDB: 1JC5 .
EC no.
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
methylmalonyl CoA epimerase
NCBI gene 84693
HGNC 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. It is routinely and incorrectly labeled as "methylmalonyl-CoA racemase". It is not a racemase because the CoA moiety has 5 other stereocenters.



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

(S)-methylmalonyl-CoA (R)-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.[ citation needed ] 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, leucine, and isoleucine. Patients with MCEED may present with life-threatening neonatal metabolic acidosis, hyperammonemia, feeding difficulties, and coma.

Related Research Articles

Citric acid cycle Metabolic pathway

The citric acid cycle (CAC) – also known as the TCA cycle or the Krebs cycle – is a series of chemical reactions used by all aerobic organisms to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism and may have originated abiogenically. Even though it is branded as a 'cycle', it is not necessary for metabolites to follow only one specific route; at least three segments of the citric acid cycle have been recognized.

Carnitine Chemical compound

Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids into mitochondria to be oxidized for energy production, and also participates in removing products of metabolism from cells. Given its key metabolic roles, carnitine is concentrated in tissues like skeletal and cardiac muscle that metabolize fatty acids as an energy source. Healthy individuals, including strict vegetarians, synthesize enough L-carnitine in vivo to not require supplementation.

Methylmalonic acidemia Medical condition

Methylmalonic acidemia, also called methylmalonic aciduria, is an autosomal recessive metabolic disorder that disrupts normal amino acid metabolism. It is a classical type of organic acidemia. The result of this condition is the inability to properly digest specific fats and proteins, which in turn leads to a buildup of a toxic level of methylmalonic acid in the blood.

Succinyl-coenzyme A, abbreviated as succinyl-CoA or SucCoA, is a thioester of succinic acid and coenzyme A.

Beta oxidation Process of fatty acid breakdown

In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycle, and NADH and FADH2, which are co-enzymes used in the electron transport chain. It is named as such because the beta carbon of the fatty acid undergoes oxidation to a carbonyl group. Beta-oxidation is primarily facilitated by the mitochondrial trifunctional protein, an enzyme complex associated with the inner mitochondrial membrane, although very long chain fatty acids are oxidized in peroxisomes.


ACADM is a gene that provides instructions for making an enzyme called acyl-coenzyme A dehydrogenase that is important for breaking down (degrading) a certain group of fats called medium-chain fatty acids.

Methylmalonyl-CoA mutase deficiency Medical condition

Methylmalonyl-CoA mutase is a mitochondrial homodimer apoenzyme that focuses on the catalysis of methylmalonyl CoA to succinyl CoA. The enzyme is bound to adenosylcobalamin, a hormonal derivative of vitamin B12 in order to function. Methylmalonyl-CoA mutase deficiency is caused by genetic defect in the MUT gene responsible for encoding the enzyme. Deficiency in this enzyme accounts for 60% of the cases of methylmalonic acidemia.

Acyl-CoA dehydrogenases (ACADs) are a class of enzymes that function to catalyze the initial step in each cycle of fatty acid β-oxidation in the mitochondria of cells. Their action results in the introduction of a trans double-bond between C2 (α) and C3 (β) of the acyl-CoA thioester substrate. Flavin adenine dinucleotide (FAD) is a required co-factor in addition to the presence of an active site glutamate in order for the enzyme to function.


Acyl-CoA dehydrogenase, C-2 to C-3 short chain is an enzyme that in humans is encoded by the ACADS gene. This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. The ACADS gene associated with short-chain acyl-coenzyme A dehydrogenase deficiency.

Methylmalonyl-CoA mutase

Methylmalonyl-CoA mutase (MCM), mitochondrial, also known as methylmalonyl-CoA isomerase, is a protein that in humans is encoded by the MUT gene. This vitamin B12-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA in humans. Mutations in MUT gene may lead to various types of methylmalonic aciduria.

Propionyl-CoA is a coenzyme A derivative of propionic acid. It is composed of a 24 total carbon chain and its production and metabolic fate depend on which organism it is present in. Several different pathways can lead to its production, such as through the catabolism of specific amino acids or the oxidation of odd-chain fatty acids. It later can be broken down by propionyl-CoA carboxylase or through the methylcitrate cycle. In different organisms, however, propionyl-CoA can be sequestered into controlled regions, to alleviate its potential toxicity through accumulation. Genetic deficiencies regarding the production and breakdown of propionyl-CoA also have great clinical and human significance.

Enoyl-CoA hydratase

Enoyl-CoA hydratase (ECH) or crotonase is an enzyme that hydrates the double bond between the second and third carbons on 2-trans/cis-enoyl-CoA:

Propionyl-CoA carboxylase (PCC) catalyses the carboxylation reaction of propionyl CoA in the mitochondrial matrix. The enzyme is biotin-dependent. The product of the reaction is (S)-methylmalonyl CoA. Propionyl CoA is the end product of metabolism of odd-chain fatty acids, and is also a metabolite of most methyl-branched fatty acids. It is also the main metabolite of valine, and together with acetyl-CoA, is a metabolite of isoleucine, as well as a methionine metabolite. Propionyl-CoA is thus of great importance as a glucose precursor. (S)-Methylmalonyl-CoA is not directly utilizable by animals; it is acted on by a racemase to give (R)-methylmalonyl-CoA. The latter is converted by methylmalonyl-CoA mutase (one of a very few Vitamin B12-dependent enzymes) to give succinyl-CoA. The latter is converted to oxaloacetate and then malate in the Krebs cycle. Export of malate into the cytosol leads to formation of oxaloacetate, phosphoenol pyruvate, and other gluconeogenic intermediates.


Acyl-CoA is a group of coenzymes that metabolize fatty acids. Acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way, fats are converted to ATP, the universal biochemical energy carrier.

Fatty acid degradation is the process in which fatty acids are broken down into their metabolites, in the end generating acetyl-CoA, the entry molecule for the citric acid cycle, the main energy supply of animals. It includes three major steps:


ACADSB is a human gene that encodes short/branched chain specific acyl-CoA dehydrogenase (SBCAD), an enzyme in the acyl CoA dehydrogenase family.

<i>alpha</i>-Ketobutyric acid Chemical compound

α-Ketobutyric acid is an organic compound with the formula CH3CH2C(O)CO2H. It is a colorless solid that melts just above room temperature. Its conjugate base α-ketobutyrate is the predominant form found in nature (near neutral pH). It results from the lysis of cystathionine. It is also one of the degradation products of threonine, produced by the catabolism of the amino acid by threonine dehydratase. It is also produced by the degradation of homocysteine and the metabolism of methionine.

In enzymology, an erythronolide synthase is an enzyme that catalyzes the chemical reaction


Acyl-coenzyme A thioesterase 4 is an enzyme that in humans is encoded by the ACOT4 gene.

Odd-chain fatty acids are those fatty acids that contain an odd number of carbon atoms. Most fatty acids are even chain, e.g. palmitic (C16) and stearic (C18). So in addition to being classified according to their saturation of unsaturation, fatty acids are also classified according to the odd vs. even numbers of constituent carbon atoms. In terms of physical properties, odd and even fatty acids are similar, generally being colorless, soluble in alcohols, and often somewhat oily. On a molecular level, the odd-chain fatty acids are biosynthesized and metabolized slightly differently from the even-chained relatives. In addition to the usual C12-C22 long chain fatty acids, some very long chain fatty acids (VLCFAs) are also known. Some of these VLCFAs are also of the odd-chain variety.


  1. "MCEE - Methylmalonyl-CoA epimerase, mitochondrial precursor - Homo sapiens (Human) - MCEE gene & protein".
  2. Europe, Protein Data Bank in. "PDB 3rmu structure summary ‹ Protein Data Bank in Europe (PDBe) ‹ EMBL-EBI".
  3. Mazumder R, Sasakawa T, Kaziro Y, Ochoa S (October 1962). "Metabolism of propionic acid in animal tissues. IX. Methylmalonyl coenzyme A racemase". The Journal of Biological Chemistry. 237: 3065–8. PMID   13934211.
  4. Overath P, Kellerman GM, Lynen F, Fritz HP, Keller HJ (1962). "[On the mechanism of the rearrangement of methylmalonyl-Co A into succinyl-Co A. II. Experiments on the mechanism of action of methylmalonyl-Co A isomerase and methylmalonyl-Co A racemase]". Biochemische Zeitschrift. 335: 500–18. PMID   14482843.
  5. Bikker H, Bakker HD, Abeling NG, Poll-The BT, Kleijer WJ, Rosenblatt DS, Waterham HR, Wanders RJ, Duran M (July 2006). "A homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE) results in mild methylmalonic aciduria". Human Mutation. 27 (7): 640–3. doi:10.1002/humu.20373. PMID   16752391. S2CID   5821956.