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Gene Review

MUT  -  methylmalonyl CoA mutase

Homo sapiens

Synonyms: MCM, Methylmalonyl-CoA isomerase, Methylmalonyl-CoA mutase, mitochondrial
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Disease relevance of MUT

  • Expression of mature human MUT cDNA in Escherichia coli at a post-induction cultivation temperature of 12 degrees C, rather than 37 degrees C, led to the folding of the majority of the synthesized protein to a soluble form, with an activity of 0.2-0.3 U/mg protein in the cell-free extract, 10-15 times higher than that in human liver homogenate [1].
  • Mapping of the mutation onto a three-dimensional model of human MCM constructed by homology with the Propionibacterium shermanii enzyme shows that it lies in a highly conserved secondary structure motif and might suggest impaired folding and/or poor stability compatible with the mut(degree) phenotype [2].
  • Methylmalonyl-CoA mutase (MCM) apoenzyme deficiency is a rare metabolic disease that may result in distinct biochemical phenotypes of methylmalonic acidemia (MMA), namely mut(o) and mut-. We analyzed a cohort of 40 MCM-deficient patients with MMA affected by either the mut(o) or the mut- form of the disease [3].
  • Vaccination with synthetic MUT 1 or MUT 2 induces CTLs that efficiently lyse CMT 64-derived clones, protects mice from CMT 64 metastasis, and affords therapy of established CMT 64 metastases [4].
  • Mutations of the human MUT S homologue 6 gene in ampullary carcinoma and gastric cancer [5].

High impact information on MUT


Chemical compound and disease context of MUT


Biological context of MUT

  • Among the missense mutations identified in the MUT gene only one, the c.970G>A (p.A324T) variant located in the substrate binding domain is likely a mut- mutation [15].
  • To date, 23 mutations have been identified at the MUT locus on the short arm of chromosome 6, causing the mut forms of MMA (mut complementation group; mut MMA, McKusick #251000) [16].
  • The maximum lod score for MUT versus HLA was 3.04 at a recombination fraction of 0.28 [17].
  • These data suggest that MUT and D6S4 loci are tightly linked and may be used as one locus in a haplotype form for linkage studies on proximal 6p and diagnostic analysis of pedigrees with mut methylmalonic acidemia [17].
  • The MUT locus exhibits consensus sequences for transcription, splicing, and polyadenylation [18].

Anatomical context of MUT

  • Distinct genotypic and phenotypic forms of methylmalonyl CoA mutase (MCM) apoenzyme deficiency can be delineated by biochemical analysis of mutant fibroblasts [19].
  • Transfection of each change into a mut0 cell line with very low MCM mRNA (GM1673) demonstrated a lack of stimulation of propionate uptake in the absence and presence of hydroxycobalamin [20].
  • The mut0 mutation resulting in methylmalonyl CoA mutase (MCM) apoenzyme deficiency and methylmalonic aciduria is characterized by undetectable enzyme activity in cell extracts and low incorporation of propionate into cultured cells which is not stimulated by hydroxycobalamin [20].
  • The activity of the other cobalamin-dependent enzyme, methylmalonyl coenzyme A mutase, in the mononuclear white blood cells, and the serum concentration of the cobalamin marker methylmalonic acid, were not altered after nitrous oxide anesthesia or methionine loading or both [21].
  • We have previously demonstrated that a mutation of the hydrophobic motif 341FNX2LLX3L350 in the C terminus of the human pituitary vasopressin V3 receptor (MUT V3R) led to it being retained in the endoplasmic reticulum (ER) [22].

Associations of MUT with chemical compounds


Other interactions of MUT

  • This led to the identification of phosphorylation sites in the carboxyl terminus of the minichromosome maintenance protein 3 (MCM3), a component of the hexameric MCM DNA helicase [27].
  • Based on results that showed that the DNA helicase activity of the MCM4-6-7 complex is negatively regulated by CDK2 phosphorylation, we suggest that the phosphorylation of MCM4 in the checkpoint control inhibits DNA replication, which includes blockage of DNA fork progression, through inactivation of the MCM complex [28].
  • MMAB encodes the enzyme ATP:cobalamin adenosyltransferase, which catalyzes the synthesis of the coenzyme adenosylcobalamin required for the activity of the mitochondrial enzyme methylmalonyl CoA mutase (MCM) [25].
  • Despite 1.7-fold higher binding and 1.8-fold higher holoparticle uptake, the selective CE uptake by MUT-EDL-expressing cells was comparable with EDL-expressing cells and was even decreased 1.3-fold with THL [29].
  • BACKGROUND: The GP.Hop (Mi.IV) phenotype expresses the MNS low-incidence antigens Mur, Hop, TSEN, MINY, and MUT [30].

Analytical, diagnostic and therapeutic context of MUT

  • Hybridization of allele-specific oligonucleotides to PCR amplified MCM exons from the proband and family members identified a clinically normal mother, half-sister, and half-brother as carriers of the G703R change in cis with both polymorphisms [20].
  • These data confirm the authenticity of the MCM cDNA clone, establish the feasibility of constituting MCM activity by gene transfer for biochemical analysis and gene therapy, and provide a preliminary picture of the genotypic spectrum underlying MCM deficiency [31].
  • Genetic and biochemical prenatal diagnosis was performed at 11 weeks of gestation in a family with a proband affected by mut methylmalonic aciduria (MMA) and homozygotes for the MUT gene c.643G>A (p.Gly215Ser) mutation [32].
  • The C3 and MUT genes, therefore, are likely to be good candidates to study as markers of bTB resistance using functional genomics in animal model systems [33].
  • Immunohistochemistry was performed using a monoclonal antibody (Ab3) to the MUT p53 and examination by light microscopy [34].


  1. Expression and kinetic characterization of methylmalonyl-CoA mutase from patients with the mut- phenotype: evidence for naturally occurring interallelic complementation. Janata, J., Kogekar, N., Fenton, W.A. Hum. Mol. Genet. (1997) [Pubmed]
  2. N219Y, a new frequent mutation among mut(degree) forms of methylmalonic acidemia in Caucasian patients. Acquaviva, C., Benoist, J.F., Callebaut, I., Guffon, N., Ogier de Baulny, H., Touati, G., Aydin, A., Porquet, D., Elion, J. Eur. J. Hum. Genet. (2001) [Pubmed]
  3. Molecular basis of methylmalonyl-CoA mutase apoenzyme defect in 40 European patients affected by mut(o) and mut- forms of methylmalonic acidemia: identification of 29 novel mutations in the MUT gene. Acquaviva, C., Benoist, J.F., Pereira, S., Callebaut, I., Koskas, T., Porquet, D., Elion, J. Hum. Mutat. (2005) [Pubmed]
  4. Identification of shared tumor-associated antigen peptides between two spontaneous lung carcinomas. Mandelboim, O., Bar-Haim, E., Vadai, E., Fridkin, M., Eisenbach, L. J. Immunol. (1997) [Pubmed]
  5. Mutations of the human MUT S homologue 6 gene in ampullary carcinoma and gastric cancer. Imai, Y., Inoue, T., Ishikawa, T. Int. J. Cancer (1998) [Pubmed]
  6. MCM proteins in DNA replication. Tye, B.K. Annu. Rev. Biochem. (1999) [Pubmed]
  7. Structure-based perspectives on B12-dependent enzymes. Ludwig, M.L., Matthews, R.G. Annu. Rev. Biochem. (1997) [Pubmed]
  8. Eukaryotic/archaeal primase and MCM proteins encoded in a bacteriophage genome. McGeoch, A.T., Bell, S.D. Cell (2005) [Pubmed]
  9. Methylmalonic aciduria without vitamin B12 deficiency in an adult sibship. Giorgio, A.J., Trowbridge, M., Boone, A.W., Patten, R.S. N. Engl. J. Med. (1976) [Pubmed]
  10. A randomized comparative trial of sequential versus alternating cyclophosphamide, doxorubicin, and cisplatin and mitomycin, lomustine, and methotrexate in metastatic non-small-cell lung cancer. Eagan, R.T., Frytak, S., Richardson, R.L., Creagan, E.T., Therneau, T.M., Coles, D.T., Jett, J.R. J. Clin. Oncol. (1988) [Pubmed]
  11. Ozone- and endotoxin-induced mucous cell metaplasias in rat airway epithelium: novel animal models to study toxicant-induced epithelial transformation in airways. Harkema, J.R., Hotchkiss, J.A. Toxicol. Lett. (1993) [Pubmed]
  12. Quantitative analysis of mitochondrial protein expression in methylmalonic acidemia by two-dimensional difference gel electrophoresis. Richard, E., Monteoliva, L., Juarez, S., Pérez, B., Desviat, L.R., Ugarte, M., Albar, J.P. J. Proteome Res. (2006) [Pubmed]
  13. Propionate metabolism in cultured human cells after overexpression of recombinant methylmalonyl CoA mutase: implications for somatic gene therapy. Wilkemeyer, M., Stankovics, J., Foy, T., Ledley, F.D. Somat. Cell Mol. Genet. (1992) [Pubmed]
  14. Phase II study of the three-drug combination of mitomycin C, CCNU, and methotrexate (MCM) in advanced non-small cell lung cancer. Eagan, R.T., Frytak, S., Richardson, R.L., Creagan, E.T., Nichols, W.C. Am. J. Clin. Oncol. (1986) [Pubmed]
  15. Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants. Martínez, M.A., Rincón, A., Desviat, L.R., Merinero, B., Ugarte, M., Pérez, B. Mol. Genet. Metab. (2005) [Pubmed]
  16. Seven novel mutations in mut methylmalonic aciduria. Adjalla, C.E., Hosack, A.R., Gilfix, B.M., Lamothe, E., Sun, S., Chan, A., Evans, S., Matiaszuk, N.V., Rosenblatt, D.S. Hum. Mutat. (1998) [Pubmed]
  17. Linkage relationships of the human methylmalonyl CoA mutase to the HLA and D6S4 loci on chromosome 6. Zoghbi, H.Y., O'Brien, W.E., Ledley, F.D. Genomics (1988) [Pubmed]
  18. Structure of the human methylmalonyl-CoA mutase (MUT) locus. Nham, S.U., Wilkemeyer, M.F., Ledley, F.D. Genomics (1990) [Pubmed]
  19. Cloning and expression of a mutant methylmalonyl coenzyme A mutase with altered cobalamin affinity that causes mut- methylmalonic aciduria. Crane, A.M., Jansen, R., Andrews, E.R., Ledley, F.D. J. Clin. Invest. (1992) [Pubmed]
  20. Cloning and expression of mutations demonstrating intragenic complementation in mut0 methylmalonic aciduria. Qureshi, A.A., Crane, A.M., Matiaszuk, N.V., Rezvani, I., Ledley, F.D., Rosenblatt, D.S. J. Clin. Invest. (1994) [Pubmed]
  21. Preoperative methionine loading enhances restoration of the cobalamin-dependent enzyme methionine synthase after nitrous oxide anesthesia. Christensen, B., Guttormsen, A.B., Schneede, J., Riedel, B., Refsum, H., Svardal, A., Ueland, P.M. Anesthesiology (1994) [Pubmed]
  22. Mechanisms of cell-surface rerouting of an endoplasmic reticulum-retained mutant of the vasopressin V1b/V3 receptor by a pharmacological chaperone. Robert, J., Auzan, C., Ventura, M.A., Clauser, E. J. Biol. Chem. (2005) [Pubmed]
  23. Mutations in mut methylmalonic acidemia: clinical and enzymatic correlations. Ledley, F.D., Rosenblatt, D.S. Hum. Mutat. (1997) [Pubmed]
  24. Co-ordinate variations in methylmalonyl-CoA mutase and methionine synthase, and the cobalamin cofactors in human glioma cells during nitrous oxide exposure and the subsequent recovery phase. Riedel, B., Fiskerstrand, T., Refsum, H., Ueland, P.M. Biochem. J. (1999) [Pubmed]
  25. Mutation and biochemical analysis of patients belonging to the cblB complementation class of vitamin B12-dependent methylmalonic aciduria. Lerner-Ellis, J.P., Gradinger, A.B., Watkins, D., Tirone, J.C., Villeneuve, A., Dobson, C.M., Montpetit, A., Lepage, P., Gravel, R.A., Rosenblatt, D.S. Mol. Genet. Metab. (2006) [Pubmed]
  26. A novel selective medium for isolation of Streptococcus mutans. Takada, K., Hirasawa, M. J. Microbiol. Methods (2005) [Pubmed]
  27. Identification of Carboxyl-terminal MCM3 Phosphorylation Sites Using Polyreactive Phosphospecific Antibodies. Shi, Y., Dodson, G.E., Mukhopadhyay, P.S., Shanware, N.P., Trinh, A.T., Tibbetts, R.S. J. Biol. Chem. (2007) [Pubmed]
  28. Identification of MCM4 as a target of the DNA replication block checkpoint system. Ishimi, Y., Komamura-Kohno, Y., Kwon, H.J., Yamada, K., Nakanishi, M. J. Biol. Chem. (2003) [Pubmed]
  29. Endothelial cell-derived lipase mediates uptake and binding of high-density lipoprotein (HDL) particles and the selective uptake of HDL-associated cholesterol esters independent of its enzymic activity. Strauss, J.G., Zimmermann, R., Hrzenjak, A., Zhou, Y., Kratky, D., Levak-Frank, S., Kostner, G.M., Zechner, R., Frank, S. Biochem. J. (2002) [Pubmed]
  30. Identification of a novel hybrid glycophorin gene encoding GP.Hop. Storry, J.R., Poole, J., Condon, J., Reid, M.E. Transfusion (2000) [Pubmed]
  31. Molecular cloning of L-methylmalonyl-CoA mutase: gene transfer and analysis of mut cell lines. Ledley, F.D., Lumetta, M., Nguyen, P.N., Kolhouse, J.F., Allen, R.H. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  32. Genetic and biochemical approach to early prenatal diagnosis in a family with mut methylmalonic aciduria. Cavicchi, C., Donati, M.A., Funghini, S., la Marca, G., Malvagia, S., Ciani, F., Poggi, G.M., Pasquini, E., Zammarchi, E., Morrone, A. Clin. Genet. (2006) [Pubmed]
  33. Characterization of selected genes upregulated in non-tuberculous European wild boar as possible correlates of resistance to Mycobacterium bovis infection. Naranjo, V., Ayoubi, P., Vicente, J., Ruiz-Fons, F., Gortazar, C., Kocan, K.M., de la Fuente, J. Vet. Microbiol. (2006) [Pubmed]
  34. Immunohistochemical expression of mutant p53 oncogene in transitional mucosa adjacent to human colon cancer. Baytner, S., Mitmaker, B., Gordon, P.H., Wang, E. Clinical and investigative medicine. Médecine clinique et experimentale. (1993) [Pubmed]
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