Methylmalonyl CoA mutase |
Rendering based on PDB 2XIJ. |
Available structures |
PDB |
Ortholog search: PDBe, RCSB |
List of PDB id codes |
2XIJ, 2XIQ, 3BIC
|
|
|
Identifiers |
Symbols |
MUT; MCM |
External IDs |
OMIM: 609058 MGI: 97239 HomoloGene: 20097 GeneCards: MUT Gene |
EC number |
5.4.99.2 |
Gene Ontology |
Molecular function |
• methylmalonyl-CoA mutase activity
• cobalamin binding
• metal ion binding
• modified amino acid binding
|
Cellular component |
• mitochondrion
• mitochondrial matrix
|
Biological process |
• fatty acid beta-oxidation
• post-embryonic development
• short-chain fatty acid catabolic process
• cellular lipid metabolic process
• small molecule metabolic process
• homocysteine metabolic process
|
Sources: Amigo / QuickGO |
|
RNA expression pattern |
|
|
More reference expression data |
Orthologs |
Species |
Human |
Mouse |
|
Entrez |
4594 |
17850 |
|
Ensembl |
ENSG00000146085 |
ENSMUSG00000023921 |
|
UniProt |
P22033 |
P16332 |
|
RefSeq (mRNA) |
NM_000255.3 |
NM_008650.3 |
|
RefSeq (protein) |
NP_000246.2 |
NP_032676.2 |
|
Location (UCSC) |
Chr 6:
49.4 – 49.43 Mb |
Chr 17:
40.93 – 40.96 Mb |
|
PubMed search |
[1] |
[2] |
|
|
methylmalonyl-CoA mutase |
Identifiers |
EC number |
5.4.99.2 |
CAS number |
9023-90-9 |
Databases |
IntEnz |
IntEnz view |
BRENDA |
BRENDA entry |
ExPASy |
NiceZyme view |
KEGG |
KEGG entry |
MetaCyc |
metabolic pathway |
PRIAM |
profile |
PDB structures |
RCSB PDB PDBe PDBsum |
Gene Ontology |
AmiGO / EGO |
Search |
PMC |
articles |
PubMed |
articles |
|
Methylmalonyl Coenzyme A mutase, also known as MCM is an enzyme that catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA and it is involved in key metabolic pathways. It requires a vitamin B12-derived prosthetic group, adenosylcobalamin, to function.
Contents
- 1 Function
- 2 Human Genetics
- 3 Pathology
- 4 Mechanism
- 5 See also
- 6 References
- 7 Further reading
- 8 External links
|
Function
The substrate of methylmalonyl-CoA mutase, methylmalonyl-CoA, is primarily derived from propionyl-CoA, a substance formed from the catabolism and digestion of isoleucine, valine, threonine, methionine, thymine, cholesterol, or odd-chain fatty acids.
The product of the enzyme, succinyl-CoA, is a key molecule of the TCA cycle.
MCM resides in the mitochondria, where a number of substances, including the branched-chain amino acids isoleucine and valine, as well as methionine, threonine, thymine and odd-chain fatty acids, are metabolized via methylmalonate semialdehyde (MMlSA) or propionyl-CoA (Pr-CoA) to a common compound - methylmalonyl-CoA (MMl-CoA).
Human Genetics
The gene encoding for this enzyme in humans is known as MUT[1].
Pathology
A deficiency of this enzyme is responsible for an inherited disorder of metabolism, Methylmalonyl-CoA mutase deficiency, which is one of the causes of methylmalonic acidemia.
Mechanism
MUT reaction mechanism begins with homolytic cleavage of AdoB12's C-Co(III) bond, the C and Co atoms each acquire one of the electrons that formed the cleaved electron pair bond. The Co ion, therefore, fluctuates between its Co(III) and Co(II) oxidation states [the two states are spectroscopically distinguishable: Co(III) is red and diamagnetic (no unpaired electrons), whereas Co(II) is yellow and paramagnetic (unpaired electrons)]. Hence, the role of coenzyme B-12 in the catalytic process is that of a reversible free radical generator. The C-Co(III) bond is well suited to this function because it is inherently weak (dissociation energy = 109 kJ/mol) and appears to be further weakened through steric interactions with the enzyme. A homolytic cleavage reaction is unusual in biology; most other biological bond cleavage reactions occur via heterolytic cleavage (in which the electron pair forming the cleaved bond is fully acquired by one of the separating atoms).
See also
References
- ^ "Entrez Gene: MUT methylmalonyl Coenzyme A mutase". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4594.
Further reading
- Ledley FD, Rosenblatt DS (1997). "Mutations in mut methylmalonic acidemia: clinical and enzymatic correlations.". Hum. Mutat. 9 (1): 1–6. doi:10.1002/(SICI)1098-1004(1997)9:1<1::AID-HUMU1>3.0.CO;2-E. PMID 8990001.
- Ludwig ML, Matthews RG (1997). "Structure-based perspectives on B12-dependent enzymes.". Annu. Rev. Biochem. 66: 269–313. doi:10.1146/annurev.biochem.66.1.269. PMID 9242908.
- Lubrano R, Elli M, Rossi M, et al. (2007). "Renal transplant in methylmalonic acidemia: could it be the best option? Report on a case at 10 years and review of the literature.". Pediatr. Nephrol. 22 (8): 1209–14. doi:10.1007/s00467-007-0460-z. PMID 17401587.
- Frenkel EP, Kitchens RL (1978). "Intracellular localization of hepatic propionyl-CoA carboxylase and methylmalonyl-CoA mutase in humans and normal and vitamin B12 deficient rats.". Br. J. Haematol. 31 (4): 501–13. doi:10.1111/j.1365-2141.1975.tb00885.x. PMID 24458.
- Crane AM, Jansen R, Andrews ER, Ledley FD (1992). "Cloning and expression of a mutant methylmalonyl coenzyme A mutase with altered cobalamin affinity that causes mut- methylmalonic aciduria.". J. Clin. Invest. 89 (2): 385–91. doi:10.1172/JCI115597. PMC 442864. PMID 1346616. //www.ncbi.nlm.nih.gov/pmc/articles/PMC442864/.
- Crane AM, Martin LS, Valle D, Ledley FD (1992). "Phenotype of disease in three patients with identical mutations in methylmalonyl CoA mutase.". Hum. Genet. 89 (3): 259–64. doi:10.1007/BF00220536. PMID 1351030.
- Raff ML, Crane AM, Jansen R, et al. (1991). "Genetic characterization of a MUT locus mutation discriminating heterogeneity in mut0 and mut- methylmalonic aciduria by interallelic complementation.". J. Clin. Invest. 87 (1): 203–7. doi:10.1172/JCI114972. PMC 295026. PMID 1670635. //www.ncbi.nlm.nih.gov/pmc/articles/PMC295026/.
- Jansen R, Ledley FD (1990). "Heterozygous mutations at the mut locus in fibroblasts with mut0 methylmalonic acidemia identified by polymerase-chain-reaction cDNA cloning.". Am. J. Hum. Genet. 47 (5): 808–14. PMC 1683687. PMID 1977311. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1683687/.
- Nham SU, Wilkemeyer MF, Ledley FD (1991). "Structure of the human methylmalonyl-CoA mutase (MUT) locus.". Genomics 8 (4): 710–6. doi:10.1016/0888-7543(90)90259-W. PMID 1980486.
- Ledley FD, Lumetta M, Nguyen PN, et al. (1988). "Molecular cloning of L-methylmalonyl-CoA mutase: gene transfer and analysis of mut cell lines.". Proc. Natl. Acad. Sci. U.S.A. 85 (10): 3518–21. doi:10.1073/pnas.85.10.3518. PMC 280243. PMID 2453061. //www.ncbi.nlm.nih.gov/pmc/articles/PMC280243/.
- Jansen R, Kalousek F, Fenton WA, et al. (1989). "Cloning of full-length methylmalonyl-CoA mutase from a cDNA library using the polymerase chain reaction.". Genomics 4 (2): 198–205. doi:10.1016/0888-7543(89)90300-5. PMID 2567699.
- Fenton WA, Hack AM, Kraus JP, Rosenberg LE (1987). "Immunochemical studies of fibroblasts from patients with methylmalonyl-CoA mutase apoenzyme deficiency: detection of a mutation interfering with mitochondrial import.". Proc. Natl. Acad. Sci. U.S.A. 84 (5): 1421–4. doi:10.1073/pnas.84.5.1421. PMC 304442. PMID 2881300. //www.ncbi.nlm.nih.gov/pmc/articles/PMC304442/.
- Zoghbi HY, O'Brien WE, Ledley FD (1989). "Linkage relationships of the human methylmalonyl CoA mutase to the HLA and D6S4 loci on chromosome 6.". Genomics 3 (4): 396–8. doi:10.1016/0888-7543(88)90135-8. PMID 2907507.
- Kolhouse JF, Utley C, Allen RH (1980). "Isolation and characterization of methylmalonyl-CoA mutase from human placenta.". J. Biol. Chem. 255 (7): 2708–12. PMID 6102092.
- Fenton WA, Hack AM, Willard HF, et al. (1982). "Purification and properties of methylmalonyl coenzyme A mutase from human liver.". Arch. Biochem. Biophys. 214 (2): 815–23. doi:10.1016/0003-9861(82)90088-1. PMID 6124211.
- Qureshi AA, Crane AM, Matiaszuk NV, et al. (1994). "Cloning and expression of mutations demonstrating intragenic complementation in mut0 methylmalonic aciduria.". J. Clin. Invest. 93 (4): 1812–9. doi:10.1172/JCI117166. PMC 294249. PMID 7909321. //www.ncbi.nlm.nih.gov/pmc/articles/PMC294249/.
- Crane AM, Ledley FD (1994). "Clustering of mutations in methylmalonyl CoA mutase associated with mut- methylmalonic acidemia.". Am. J. Hum. Genet. 55 (1): 42–50. PMC 1918235. PMID 7912889. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1918235/.
- Janata J, Kogekar N, Fenton WA (1998). "Expression and kinetic characterization of methylmalonyl-CoA mutase from patients with the mut- phenotype: evidence for naturally occurring interallelic complementation.". Hum. Mol. Genet. 6 (9): 1457–64. doi:10.1093/hmg/6.9.1457. PMID 9285782.
External links
- GeneReviews/NIH/NCBI/UW entry on Methylmalonic Acidemia
- Methylmalonyl-CoA+Mutase at the US National Library of Medicine Medical Subject Headings (MeSH)
Isomerase: mutases (EC 5.4)
|
|
5.4.2 Phosphomutases |
Phosphoglycerate mutase · Bisphosphoglycerate mutase · Phosphoglucomutase · Phosphomannomutase (PMM2)
|
|
5.4.99 Other groups |
Methylmalonyl-CoA mutase · Lanosterol synthase
|
|
- B
- enzm
- 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 2.7.10
- 2.7.11-12
- 3.1
- 4.1
- 5.1
- 6.1-3
|
|
|
|
Metabolism: amino acid metabolism · synthesis and catabolism enzymes (essential in CAPS)
|
|
K→acetyl-CoA |
LYSINE→
|
- Saccharopine dehydrogenase
- Glutaryl-CoA dehydrogenase
|
|
LEUCINE→
|
- Branched chain aminotransferase
- Branched-chain alpha-keto acid dehydrogenase complex
- Isovaleryl coenzyme A dehydrogenase
- Methylcrotonyl-CoA carboxylase
- Methylglutaconyl-CoA hydratase
- 3-hydroxy-3-methylglutaryl-CoA lyase
|
|
TRYPTOPHAN→
|
- Indoleamine 2,3-dioxygenase/Tryptophan 2,3-dioxygenase
- Arylformamidase
- Kynureninase
- 3-hydroxyanthranilate oxidase
- Aminocarboxymuconate-semialdehyde decarboxylase
- Aminomuconate-semialdehyde dehydrogenase
|
|
PHENYLALANINE→tyrosine→
|
(see below)
|
|
|
G |
G→pyruvate
→citrate
|
glycine→serine→
|
- Serine hydroxymethyltransferase
- Serine dehydratase
- glycine→creatine: Guanidinoacetate N-methyltransferase
- Creatine kinase
|
|
alanine→
|
|
|
cysteine→
|
|
|
threonine→
|
- L-threonine dehydrogenase
|
|
|
G→glutamate→
α-ketoglutarate
|
|
HISTIDINE→
|
- Histidine ammonia-lyase
- Urocanate hydratase
- Formiminotransferase cyclodeaminase
|
|
proline→
|
- Proline oxidase
- Pyrroline-5-carboxylate reductase
- 1-Pyrroline-5-carboxylate dehydrogenase/ALDH4A1
- PYCR1
|
|
arginine→
|
- Ornithine aminotransferase
- Ornithine decarboxylase
- Agmatinase
|
|
→alpha-ketoglutarate→TCA
|
|
|
Other
|
- cysteine+glutamate→glutathione: Gamma-glutamylcysteine synthetase
- Glutathione synthetase
- Gamma-glutamyl transpeptidase
- glutamate→glutamine: Glutamine synthetase
- Glutaminase
|
|
|
G→propionyl-CoA→
succinyl-CoA
|
VALINE→
|
- Branched chain aminotransferase
- Branched-chain alpha-keto acid dehydrogenase complex
- Enoyl-CoA hydratase
- 3-hydroxyisobutyryl-CoA hydrolase
- 3-hydroxyisobutyrate dehydrogenase
- Methylmalonate semialdehyde dehydrogenase
|
|
ISOLEUCINE→
|
- Branched chain aminotransferase
- Branched-chain alpha-keto acid dehydrogenase complex
- 3-hydroxy-2-methylbutyryl-CoA dehydrogenase
|
|
METHIONINE→
|
- generation of homocysteine: Methionine adenosyltransferase
- Adenosylhomocysteinase
- regeneration of methionine: Methionine synthase/Homocysteine methyltransferase
- Betaine-homocysteine methyltransferase
- conversion to cysteine: Cystathionine beta synthase
- Cystathionine gamma-lyase
|
|
THREONINE→
|
|
|
→succinyl-CoA→TCA
|
- Propionyl-CoA carboxylase
- Methylmalonyl CoA epimerase
- Methylmalonyl-CoA mutase
|
|
|
G→fumarate
|
|
PHENYLALANINE→tyrosine→
|
- Phenylalanine hydroxylase
- Tyrosine aminotransferase
- 4-Hydroxyphenylpyruvate dioxygenase
- Homogentisate 1,2-dioxygenase
- Fumarylacetoacetate hydrolase
- tyrosine→melanin: Tyrosinase
|
|
|
G→oxaloacetate
|
|
asparagine→aspartate→
|
- Asparaginase/Asparagine synthetase
- Aspartate transaminase
|
|
|
|
|
mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m
|
k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon
|
m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)
|
|
|
|
Metabolism: Citric acid cycle enzymes
|
|
Cycle |
- Citrate synthase
- Aconitase
- Isocitrate dehydrogenase
- Oxoglutarate dehydrogenase
- Succinyl CoA synthetase
- Succinate dehydrogenase (SDHA)
- Fumarase
- Malate dehydrogenase and ETC
|
|
Anaplerotic |
to acetyl-CoA
|
- Pyruvate dehydrogenase complex (E1, E2, E3)
- (regulated by Pyruvate dehydrogenase kinase and Pyruvate dehydrogenase phosphatase)
|
|
to α-ketoglutaric acid
|
|
|
to succinyl-CoA
|
|
|
to oxaloacetate
|
- Pyruvate carboxylase
- Aspartate transaminase
|
|
|
Mitochondrial
electron transport chain/
oxidative phosphorylation |
Primary
|
- Complex I/NADH dehydrogenase
- Complex II/Succinate dehydrogenase
- Coenzyme Q
- Complex III/Coenzyme Q - cytochrome c reductase
- Cytochrome c
- Complex IV/Cytochrome c oxidase
- Coenzyme Q10 synthesis: COQ2
- COQ3
- COQ4
- COQ5
- COQ6
- COQ7
- COQ9
- COQ10A
- COQ10B
- PDSS1
- PDSS2
|
|
Other
|
- Alternative oxidase
- Electron-transferring-flavoprotein dehydrogenase
|
|
|
|
mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m
|
k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon
|
m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)
|
|
|
|