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Methylmalonyl-CoA mutase: Wikis

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Methylmalonyl Coenzyme A mutase
Identifiers
Symbols MUT; MCM
External IDs OMIM609058 MGI97239 HomoloGene20097 GeneCards: MUT Gene
EC number 5.4.99.2
RNA expression pattern
PBB GE MUT 202959 at tn.png
PBB GE MUT 202960 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4594 17850
Ensembl ENSG00000146085 ENSMUSG00000023921
UniProt P22033 Q3UFU2
RefSeq (mRNA) NM_000255 NM_008650
RefSeq (protein) NP_000246 NP_032676
Location (UCSC) Chr 6:
49.51 - 49.54 Mb
Chr 17:
40.4 - 40.43 Mb
PubMed search [1] [2]

Methylmalonyl Coenzyme A mutase, also known as MUT, is a human enzyme.[1]

The protein encoded by this gene is an enzyme involved in key metabolic pathways. It catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. It requires its Vitamin B12 derived prosthetic group, adenosylcobalamin, to 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.

Contents

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.

Function

MUT resides in the mitochondria where a number of substances, including the branched-chain amino acids Ile and Val, as well as Met, Thr, thymine and odd-chain FAs are metabolized via Methylmalonate semialdehyde (MMlSA) or Propionyl-CoA (Pr-CoA) to a common compound - Methyl-malonyl-CoA (MMl-CoA).

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). >

MUT's reaction mechanism

References

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. PMID 1346616.  
  • 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. PMID 1670635.  
  • 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. PMID 1977311.  
  • 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. PMID 2453061.  
  • 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. PMID 2881300.  
  • 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. PMID 7909321.  
  • 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. PMID 7912889.  
  • 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.  

See also

External links

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