Methylmalonyl-CoA mutase
| MMUT | |||
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Gene ontology | |||
| Molecular function | |||
| Cellular component | |||
| Biological process | |||
| Sources:Amigo / QuickGO | |||
Ensembl | |||||||||
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| RefSeq (mRNA) | |||||||||
| RefSeq (protein) | |||||||||
| Location (UCSC) | Chr 6: 49.43 – 49.46 Mb | Chr 17: 41.25 – 41.27 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
| methylmalonyl-CoA mutase | |||||||||
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| Identifiers | |||||||||
ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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Methylmalonyl-CoA mutase (methylmalonic aciduria.[5]
MCM was first identified in
holoenzyme form.[6]
Structure
Gene
The MUT gene lies on the
exons, spanning over 35kb.[7]
Protein
The mature enzyme is a homodimer with the N-terminal CoA binding domain and the C- terminal cobalamin-binding domain.[8]
Function
Methylmalonyl-CoA mutase is expressed in high concentrations in the
fatty acids
, are metabolized via methylmalonate semialdehyde (MMlSA) or propionyl-CoA (Pr-CoA) to a common compound - methylmalonyl-CoA (MMl-CoA).
MCM catalyzes the reversible isomerisation of l‐methylmalonyl‐CoA to succinyl‐CoA, requiring cobalamin (vitamin B12) in the form of adenosylcobalamin (AdoCbl) as a cofactor. As an important step in propionate catabolism, this reaction is required for the degradation of odd-chain tricarboxylic acid cycle.[10]
Methylmalonyl-CoA mutase catalyzes the following reaction:
L-methylmalonyl-CoA
|
methylmalonyl-CoA mutase | Succinyl-CoA | |
|
| ||
| |||
| methylmalonyl-CoA mutase | |||
The substrate of methylmalonyl-CoA mutase,
tricarboxylic acid cycle
.
Clinical significance
A deficiency of this enzyme is responsible for an inherited disorder of metabolism,
autosomal recessive inherited inborn error of metabolism, characterized by recurrent episodes of vomiting, lethargy, profound ketoacidosis, hyperammonemia, and pancytopenia in infancy, and may cause early death. Complications include cardiomyopathy, metabolic stroke, pancreatitis, and progressive renal failure.[5][11]
Either mutations to the gene MUT (encodes methylmalonyl-CoA mutase), or MMAA (encodes a chaperone protein of methylmalonyl-CoA mutase, MMAA protein) can lead to methylmalonyl acidemia.nonsense mutations comprise a significant remaining fraction (approximately 14%)[13]
Common treatment methods for MMA include a
renal disease of methylmalonic acidemia. However, detrimental neurological effects can continue to plague patients even after a successful operation. It is thought that this is due to the widespread presence of methylmalonyl-CoA mutase throughout the central nervous system. Due to the loss of functionality of the enzyme, substrate levels build up in the CNS. The substrate, L-methylmalonyl-CoA hydrolyzes to form methylmalonate (methylmalonic acid), a neurotoxic dicarboxylic acid that, due to the poor dicarboxylic acid transport capacities of the blood-brain barrier, is effectively trapped within the CNS, leading to neurological debilitation. To combat these effects perioperative anti-catabolic regimes and no diet discontinuation are recommended.[6]
The
murine model has proven an adequate and accurate way of studying the effects of MMA, and potential treatment methods.[14][15]
Mechanism
The MCM reaction mechanism begins with homolytic cleavage of AdoB12's C-
free radical. The C-Co(III) bond is weak, with a dissociation energy = 109 kJ/mol, and appears to be further weakened through steric interactions with the enzyme. The homolytic
reaction is unusual in biology, as is the presence of a metal-carbon bond.
Methylmalonyl-CoA mutase is a member of the
corrin ring, an upper axial ligand (β-axial ligand), and a lower axial ligand (α-axial ligand). In methylmalonyl-CoA mutase, the β-axial ligand 5’-deoxy-5’-adenosine reversibly dissociated to give the deoxyadenosyl radical. The α-axial ligand 5,6-dimethylbenzimidazole (DMB) is involved in organizing the active site to enable histidine-610 to bond with Co, instead of DMB (the reason for the ‘DMB-off’/’His-on’ notation).[16] Binding of histidine-610 residue increases the rate of homolytic β-axial ligand – Co bond breakage by a factor of 1012.[17]
Other important residues of methylmalonyl-CoA mutase include Histidine-244, which acts as a general acid near the substrate and shields the radical species from side reactions involving oxygen,Glutamate-370, whose hydrogen bond with the 2’-OH group of the ribose of the β-axial ligand forces interaction between the β-axial ligand radical species and the substrate,[21] and tyrosine-89 which stabilizes reactive radical intermediates and accounts for the stereo-selectivity of the enzyme.[18][22]
The processing protein,
Interactions
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000146085 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000023921 – 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.
- ^ PMID 26449400.
- ^ S2CID 34612963.
- PMID 16182581.
- ^ PMID 8643613.
- PMID 15781192.
- ^ PMID 25125334.
- PMID 22727635.
- ^ PMID 21138732.
- PMID 23041189.
- PMID 23046887.
- PMID 23898205.
- ^ PMID 22661206.
- PMID 11893736.
- ^ PMID 10387043.
- PMID 9655823.
- PMID 10551831.
- PMID 22945861.
- PMID 9772164.
- ^ PMID 20876572.
- PMID 16641088.
- PMID 7989334.
Further reading
- Ledley FD, Rosenblatt DS (1997). "Mutations in mut methylmalonic acidemia: clinical and enzymatic correlations". Human Mutation. 9 (1): 1–6. S2CID 41661834.
- Ludwig ML, Matthews RG (1997). "Structure-based perspectives on B12-dependent enzymes". Annual Review of Biochemistry. 66: 269–313. PMID 9242908.
- Lubrano R, Elli M, Rossi M, Travasso E, Raggi C, Barsotti P, Carducci C, Berloco P (August 2007). "Renal transplant in methylmalonic acidemia: could it be the best option? Report on a case at 10 years and review of the literature". Pediatric Nephrology. 22 (8): 1209–14. S2CID 24610554.
- Frenkel EP, Kitchens RL (December 1975). "Intracellular localization of hepatic propionyl-CoA carboxylase and methylmalonyl-CoA mutase in humans and normal and vitamin B12 deficient rats". British Journal of Haematology. 31 (4): 501–13. S2CID 1232083.
- Crane AM, Jansen R, Andrews ER, Ledley FD (February 1992). "Cloning and expression of a mutant methylmalonyl coenzyme A mutase with altered cobalamin affinity that causes mut- methylmalonic aciduria". The Journal of Clinical Investigation. 89 (2): 385–91. PMID 1346616.
- Crane AM, Martin LS, Valle D, Ledley FD (May 1992). "Phenotype of disease in three patients with identical mutations in methylmalonyl CoA mutase". Human Genetics. 89 (3): 259–64. S2CID 5624280.
- Raff ML, Crane AM, Jansen R, Ledley FD, Rosenblatt DS (January 1991). "Genetic characterization of a MUT locus mutation discriminating heterogeneity in mut0 and mut- methylmalonic aciduria by interallelic complementation". The Journal of Clinical Investigation. 87 (1): 203–7. PMID 1670635.
- Jansen R, Ledley FD (November 1990). "Heterozygous mutations at the mut locus in fibroblasts with mut0 methylmalonic acidemia identified by polymerase-chain-reaction cDNA cloning". American Journal of Human Genetics. 47 (5): 808–14. PMID 1977311.
- Nham SU, Wilkemeyer MF, Ledley FD (December 1990). "Structure of the human methylmalonyl-CoA mutase (MUT) locus". Genomics. 8 (4): 710–6. PMID 1980486.
- Ledley FD, Lumetta M, Nguyen PN, Kolhouse JF, Allen RH (May 1988). "Molecular cloning of L-methylmalonyl-CoA mutase: gene transfer and analysis of mut cell lines". Proceedings of the National Academy of Sciences of the United States of America. 85 (10): 3518–21. PMID 2453061.
- Jansen R, Kalousek F, Fenton WA, Rosenberg LE, Ledley FD (February 1989). "Cloning of full-length methylmalonyl-CoA mutase from a cDNA library using the polymerase chain reaction". Genomics. 4 (2): 198–205. PMID 2567699.
- Fenton WA, Hack AM, Kraus JP, Rosenberg LE (March 1987). "Immunochemical studies of fibroblasts from patients with methylmalonyl-CoA mutase apoenzyme deficiency: detection of a mutation interfering with mitochondrial import". Proceedings of the National Academy of Sciences of the United States of America. 84 (5): 1421–4. PMID 2881300.
- Zoghbi HY, O'Brien WE, Ledley FD (November 1988). "Linkage relationships of the human methylmalonyl CoA mutase to the HLA and D6S4 loci on chromosome 6". Genomics. 3 (4): 396–8. PMID 2907507.
- Kolhouse JF, Utley C, Allen RH (April 1980). "Isolation and characterization of methylmalonyl-CoA mutase from human placenta". The Journal of Biological Chemistry. 255 (7): 2708–12. PMID 6102092.
- Fenton WA, Hack AM, Willard HF, Gertler A, Rosenberg LE (April 1982). "Purification and properties of methylmalonyl coenzyme A mutase from human liver". Archives of Biochemistry and Biophysics. 214 (2): 815–23. PMID 6124211.
- Qureshi AA, Crane AM, Matiaszuk NV, Rezvani I, Ledley FD, Rosenblatt DS (April 1994). "Cloning and expression of mutations demonstrating intragenic complementation in mut0 methylmalonic aciduria". The Journal of Clinical Investigation. 93 (4): 1812–9. PMID 7909321.
- Crane AM, Ledley FD (July 1994). "Clustering of mutations in methylmalonyl CoA mutase associated with mut- methylmalonic acidemia". American Journal of Human Genetics. 55 (1): 42–50. PMID 7912889.
- Janata J, Kogekar N, Fenton WA (September 1997). "Expression and kinetic characterization of methylmalonyl-CoA mutase from patients with the mut- phenotype: evidence for naturally occurring interallelic complementation". Human Molecular Genetics. 6 (9): 1457–64. PMID 9285782.
External links
- GeneReviews/NIH/NCBI/UW entry on Methylmalonic Acidemia
- Methylmalonyl-CoA+Mutase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
