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Gene Review

MMAA  -  methylmalonic aciduria (cobalamin...

Homo sapiens

Synonyms: Methylmalonic aciduria type A protein, mitochondrial, cblA
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Disease relevance of MMAA

  • In Methylobacterium extorquens AM1, a mutant defective in the MMAA homolog meaB was unable to grow on C(1) and C(2) compounds because of the inability to convert methylmalonyl-CoA to succinyl-CoA (Korotkova N., Chistoserdova, L., Kuksa, V., and Lidstrom, M. E. (2002) J. Bacteriol. 184, 1750-1758) [1].

High impact information on MMAA

  • There were highly significant differences in plasma concentrations and activities of paraoxonase between genotypes defined by the 54 polymorphism: MMAA, MLAA, LLAA; protein, 65.3+/-18.0, 77.9+/-18.0, 93.5+/-26.0 microg/ml; P < 0.0001: activity (phenylacetate), 48.6+/-13.5, 64.1+/-14.5, 68.1+/-13.0 U/ml; P < 0.0001 [2].
  • A patient, formerly identified as belonging to the cblA complementation group of vitamin B12 disorders but lacking mutations in the affected gene, MMAA, was tested for mutations in the MCEE gene [3].
  • In the MMAA patients analyzed, frameshift mutations are prevalent [4].
  • The MMAA protein likely transports Cbl into the mitochondria for adenosylcobalamin synthesis, while the MMAB protein appears to be an adenosyltransferase [5].
  • When human alveolar epithelial type II (L-132) cells in culture were exposed to either one of these three arsenic compounds, DNA single-strand breaks resulting from the inhibition of repair polymerization were remarkably produced by exposure to DMAA at 5 to 100 microM, while not by that to ARS and MMAA even at 100 microM [6].

Biological context of MMAA

  • Genomic DNA from 37 cblA patients, diagnosed on the basis of cellular adenosylcobalamin synthesis, methylmalonyl-coenzyme A (CoA) mutase function, and complementation analysis, was analyzed for deleterious mutations in the MMAA gene by DNA sequencing of exons and flanking sequences [7].
  • Mutations in the MMAA gene on human chromosome 4q31.21 result in vitamin B12-responsive methylmalonic aciduria (cblA complementation group) due to deficiency in the synthesis of adenosylcobalamin [7].
  • When L-132 cells were exposed to 100 microM MMAA in the presence of 10 mM S-adenosyl-L-methionine (SAM), which is a well-known methyl-group donor in metabolic methylation of arsenics, DNA repair synthesis was induced along with an increase in the amount of dimethylarsenic in the cells [6].
  • In 160 subjects with no occupational exposure to arsenic compounds, InAs , MMAA , DMAA each accounted for about 10% of the total arsenic urinary excretion (17.2 +/- 11.1 micrograms/1), thus indicating that in the normal population over 60% of arsenic in urine is present in other organic forms [8].

Associations of MMAA with chemical compounds

  • The total content of arsenic and of its inorganic (As(III) and As(V)) and organic (monomethylarsonic acid, MMAA, and dimethylarsinic acid, DMAA) species were determined in a set of 21 alcoholic and alcohol-free beer samples using the technique of Hydride Generation Atomic Absorption Spectrometry [9].
  • A 4 x 3 factorial experiment was conducted with four As species [arsenite, arsenate, methylarsonic acid (MMAA), dimethylarsinic acid (DMAA)] and three As concentrations (1.0, 2.0, and 5.0 mg L(-)(1)) [10].
  • Organic arsenicals, especially MMAA, were clearly phytotoxic to this turnip cultivar [10].
  • The mobile phase containing 2 mM NaH(2)PO(4) and 0.2 mM EDTA at pH 6 allowed adequate separation of four As species (As(III), As(V), MMAA, DMAA) in less than 10 min [11].


  1. MeaB is a component of the methylmalonyl-CoA mutase complex required for protection of the enzyme from inactivation. Korotkova, N., Lidstrom, M.E. J. Biol. Chem. (2004) [Pubmed]
  2. Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes. Garin, M.C., James, R.W., Dussoix, P., Blanché, H., Passa, P., Froguel, P., Ruiz, J. J. Clin. Invest. (1997) [Pubmed]
  3. Homozygous nonsense mutation in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: a novel cause of mild methylmalonic aciduria. Dobson, C.M., Gradinger, A., Longo, N., Wu, X., Leclerc, D., Lerner-Ellis, J., Lemieux, M., Belair, C., Watkins, D., Rosenblatt, D.S., Gravel, R.A. Mol. Genet. Metab. (2006) [Pubmed]
  4. 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]
  5. Mutation analysis of the MMAA and MMAB genes in Japanese patients with vitamin B(12)-responsive methylmalonic acidemia: identification of a prevalent MMAA mutation. Yang, X., Sakamoto, O., Matsubara, Y., Kure, S., Suzuki, Y., Aoki, Y., Suzuki, Y., Sakura, N., Takayanagi, M., Iinuma, K., Ohura, T. Mol. Genet. Metab. (2004) [Pubmed]
  6. Metabolic methylation is a possible genotoxicity-enhancing process of inorganic arsenics. Yamanaka, K., Hayashi, H., Tachikawa, M., Kato, K., Hasegawa, A., Oku, N., Okada, S. Mutat. Res. (1997) [Pubmed]
  7. Mutations in the MMAA gene in patients with the cblA disorder of vitamin B12 metabolism. Lerner-Ellis, J.P., Dobson, C.M., Wai, T., Watkins, D., Tirone, J.C., Leclerc, D., Doré, C., Lepage, P., Gravel, R.A., Rosenblatt, D.S. Hum. Mutat. (2004) [Pubmed]
  8. Significance of arsenic metabolic forms in urine. Part I: Chemical speciation. Buratti, M., Calzaferri, G., Caravelli, G., Colombi, A., Maroni, M., Foà, V. International journal of environmental analytical chemistry. (1984) [Pubmed]
  9. Presence and distribution of arsenical species in beers. Herce-Pagliai, C., González, G., Camean, A.M., Repetto, M. Food additives and contaminants. (1999) [Pubmed]
  10. Arsenic toxicity and accumulation in turnip as affected by arsenic chemical speciation. Carbonell-Barrachina, A.A., Burló, F., Valero, D., López, E., Martínez-Romero, D., Martínez-Sánchez, F. J. Agric. Food Chem. (1999) [Pubmed]
  11. A study of method robustness for arsenic speciation in drinking water samples by anion exchange HPLC-ICP-MS. Day, J.A., Montes-Bayón, M., Vonderheide, A.P., Caruso, J.A. Analytical and bioanalytical chemistry. (2002) [Pubmed]
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