Methylmalonyl CoA epimerase
| MCEE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | MCEE, GLOD2, methylmalonyl-CoA epimerase, MCE, MMCE | |||||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 608419; MGI: 1920974; GeneCards: MCEE | |||||||||||||||||||||||||||||||||||||||||||||||||||||
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| methylmalonyl CoA epimerase | |||||||||
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| Identifiers | |||||||||
| EC no. | 5.1.99.1 | ||||||||
| Databases | |||||||||
| BRENDA | enzyme data | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | enzyme entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| Rhea | reactions | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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Methylmalonyl CoA epimerase (EC 5.1.99.1) is an enzyme which in humans is encoded by the MCEE gene. It is involved in the process of breaking down fatty acids (fatty acid catabolism).[5] It is also frequently called methylmalonyl-CoA racemase, but this is technically inaccurate. It is not a racemase because the CoA moiety has 5 other stereocenters. Outside of humans, the term "Methylmalonyl-CoA epimerase" is sometimes used more broadly to refer to any enzyme that can catalyze the same reaction, such as the multifunctional enzyme called "Ethylmalonyl-CoA/methylmalonyl-CoA epimerase", which was found in a type of bacteria.[6]
Structure
[edit]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.[7] Several natural variants in amino acid sequences exist. The structure of the MCEE protein has been resolved by X-ray crystallography[8] at 1.8-angstrom resolution.
Function
[edit]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 catalyses the chemical reaction that converts (S)-methylmalonyl-CoA to the (R) form:[9][10]
- (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
[edit]Mutations in the MCEE gene causes methymalonyl-CoA epimerase deficiency (MCEED),[11] 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.
References
[edit]- 1 2 3 GRCh38: Ensembl release 89: ENSG00000124370 – Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000033429 – Ensembl, May 2017
- ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ "Q96PE7 · MCEE_HUMAN". uniprot.org. UniProt consortium. Retrieved 2026-08-12.
- ↑ "Q3IZP4 · EPI_CERS4". uniprot.org. UniProt consortium. Retrieved 2026-08-12.
- ↑ "MCEE - Methylmalonyl-CoA epimerase, mitochondrial precursor - Homo sapiens (Human) - MCEE gene & protein". www.uniprot.org.
- ↑ Europe, Protein Data Bank in. "PDB 3rmu structure summary ‹ Protein Data Bank in Europe (PDBe) ‹ EMBL-EBI". www.ebi.ac.uk.
- ↑ 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 (10): 3065–8. doi:10.1016/S0021-9258(18)50121-6. PMID 13934211.
- ↑ 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.
- ↑ 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.
External links
[edit]- methylmalonyl-CoA+epimerase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
