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Gene Review

MTR  -  5-methyltetrahydrofolate-homocysteine...

Homo sapiens

Synonyms: 5-methyltetrahydrofolate--homocysteine methyltransferase, HMAG, MS, Methionine synthase, Vitamin-B12 dependent methionine synthase, ...
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Disease relevance of MTR


Psychiatry related information on MTR


High impact information on MTR

  • In methionine synthase, the best studied of the methyltransferases, the histidine ligand appears to be required for competent methyl transfer between methyl-tetrahydrofolate and homocysteine but dissociates for reductive reactivation of the inactive oxidized enzyme [10].
  • Electrospray mass spectrometry (ESP-MS) of EoCPs revealed for EoCP-2 a molecular mass of 7,862.8 +/- 1.1 daltons, which is 15.8 mass units higher than the calculated value of RANTES, indicating that EoCP-2 is identical to the full-length cytokine, and oxygenation, probably at methionine residue number 64, has taken place [11].
  • Upon ESP-MS, EoCP-1 showed an average molecular mass of 8,355 +/- 10 daltons, suggesting O-glycosylation at these serine residues [11].
  • The results showed that there was a large variance in M and MTR among these glucose-tolerant subjects [12].
  • There was no significant, independent correlation between age or degree of obesity and M or MTR [12].

Chemical compound and disease context of MTR

  • It was hypothesized that polymorphisms of MTR and MTRR are associated with lung cancer risk and interact with dietary intake of folate-related nutrients in lung cancer etiology [2].
  • The MS gly/gly polymorphism was also not significantly associated with risk of colorectal adenomas (RR = 0.66, 95% CI 0.26-1.70) [13].
  • In this study, we examined the relationship of a polymorphism (2756A-->G, asp-->gly) in the gene (MTR) for methionine synthase, another important enzyme in the same folate/methionine/homocyst(e)ine metabolic pathway, with risk of colorectal cancer among 356 cases and 476 cancer-free controls [8].
  • METHODS: We evaluated homocysteine, folic acid and vitamin B(12) concentrations, and the mutations 677C>T and 1298A>C in MTHFR, 844ins68 in CBS and 2756A>G in MTR genes in 58 patients with congenital heart defects, 38 control subjects, and mothers of 49 patients and 26 controls [14].
  • The crystal structure of the C-terminal domain of the Escherichia coli MS predicts that the Pro to Leu mutation could disrupt activation since it is embedded in a sequence that makes direct contacts with the bound AdoMet [15].

Biological context of MTR


Anatomical context of MTR


Associations of MTR with chemical compounds

  • This study provides no evidence that these common MTR and MTRR mutations are associated with alterations in plasma homocysteine [23].
  • After a methionine load, a weak positive association was observed between change in homocysteine after a methionine load and the number of mutant MTR alleles (P-trend=0.04), but this association was not statistically significant according to the overall F-statistic (P=0.12) [23].
  • Apoenzyme alone is quite unstable at 37 degrees C. MSR also is able to reduce aquacobalamin to cob(II)alamin in the presence of NADPH, and this reduction leads to stimulation of the conversion of apoMS and aquacobalamin to MS holoenzyme [3].
  • METHOD: We developed a high-level multiplex genotyping method based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for the detection of 12 polymorphisms in 8 genes involved in folate or Hcy metabolism [24].
  • The methionine synthase gene (MTR) mutation is an A to G substitution, 2756A-->G, which converts an aspartate to a glycine codon [23].

Physical interactions of MTR

  • Electron transfer from MSR to the cob(II)alamin cofactor coupled with methyl transfer from S-adenosyl methionine returns MS to the active methylcob(III)alamin state [25].

Enzymatic interactions of MTR


Regulatory relationships of MTR


Other interactions of MTR

  • Individuals with MTR 2756AA had 2-fold higher risk of FL, and subjects not having at least one TYMS 2R allele showed a 2-fold higher risk of FL [16].
  • RESULTS: The MTHFR 677T [odds ratio (OR) 0.63, 95% CI 0.2-1.7] and MTR 2756G (OR 0.74, 95% CI 0.4-1.4) alleles were associated with moderate reduction in risk of OSCM whereas the CBS 844ins68 allele (OR 1.4, 0.7-2.4) was associated with an increased risk [32].
  • Further, MS 2756AG individuals who were SHMT1 1420CT/TT had a 5.6-fold reduction in ALL risk (OR = 0.18; 95% CI, 0.05-0.63) [33].
  • Neither MTR D919G nor RFC 80G>A polymorphisms were associated with altered colon cancer risk [34].
  • Ethanol feeding alone reduced the activities of methionine synthase (MS) and MATIII and increased the activity of GNMT [35].

Analytical, diagnostic and therapeutic context of MTR


  1. Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association. O'Leary, V.B., Mills, J.L., Pangilinan, F., Kirke, P.N., Cox, C., Conley, M., Weiler, A., Peng, K., Shane, B., Scott, J.M., Parle-McDermott, A., Molloy, A.M., Brody, L.C. Mol. Genet. Metab. (2005) [Pubmed]
  2. Polymorphisms of methionine synthase and methionine synthase reductase and risk of lung cancer: a case-control analysis. Shi, Q., Zhang, Z., Li, G., Pillow, P.C., Hernandez, L.M., Spitz, M.R., Wei, Q. Pharmacogenet. Genomics (2005) [Pubmed]
  3. Human methionine synthase reductase is a molecular chaperone for human methionine synthase. Yamada, K., Gravel, R.A., Toraya, T., Matthews, R.G. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  4. Methionine synthase genetic polymorphism MS A2756G alters susceptibility to follicular but not diffuse large B-cell non-Hodgkin's lymphoma or multiple myeloma. Lincz, L.F., Scorgie, F.E., Kerridge, I., Potts, R., Spencer, A., Enno, A. Br. J. Haematol. (2003) [Pubmed]
  5. Association study of four polymorphisms in three folate-related enzyme genes with non-obstructive male infertility. Lee, H.C., Jeong, Y.M., Lee, S.H., Cha, K.Y., Song, S.H., Kim, N.K., Lee, K.W., Lee, S. Hum. Reprod. (2006) [Pubmed]
  6. Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin's lymphoma in adults. Gemmati, D., Ongaro, A., Scapoli, G.L., Della Porta, M., Tognazzo, S., Serino, M.L., Di Bona, E., Rodeghiero, F., Gilli, G., Reverberi, R., Caruso, A., Pasello, M., Pellati, A., De Mattei, M. Cancer Epidemiol. Biomarkers Prev. (2004) [Pubmed]
  7. Association of IL-1 RN*2 allele and methionine synthase 2756 AA genotype with dementia severity of sporadic Alzheimer's disease. Bosco, P., Guéant-Rodríguez, R.M., Anello, G., Romano, A., Namour, B., Spada, R.S., Caraci, F., Tringali, G., Ferri, R., Guéant, J.L. J. Neurol. Neurosurg. Psychiatr. (2004) [Pubmed]
  8. A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. Ma, J., Stampfer, M.J., Christensen, B., Giovannucci, E., Hunter, D.J., Chen, J., Willett, W.C., Selhub, J., Hennekens, C.H., Gravel, R., Rozen, R. Cancer Epidemiol. Biomarkers Prev. (1999) [Pubmed]
  9. Congenital errors of folate metabolism. Zittoun, J. Baillieres Clin. Haematol. (1995) [Pubmed]
  10. Structure-based perspectives on B12-dependent enzymes. Ludwig, M.L., Matthews, R.G. Annu. Rev. Biochem. (1997) [Pubmed]
  11. Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils. Kameyoshi, Y., Dörschner, A., Mallet, A.I., Christophers, E., Schröder, J.M. J. Exp. Med. (1992) [Pubmed]
  12. Relationship between obesity and maximal insulin-stimulated glucose uptake in vivo and in vitro in Pima Indians. Bogardus, C., Lillioja, S., Mott, D., Reaven, G.R., Kashiwagi, A., Foley, J.E. J. Clin. Invest. (1984) [Pubmed]
  13. A prospective study of methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms, and risk of colorectal adenoma. Chen, J., Giovannucci, E., Hankinson, S.E., Ma, J., Willett, W.C., Spiegelman, D., Kelsey, K.T., Hunter, D.J. Carcinogenesis (1998) [Pubmed]
  14. Homocysteine concentrations and molecular analysis in patients with congenital heart defects. Galdieri, L.C., Arrieta, S.R., Silva, C.M., Pedra, C.A., D'Almeida, V. Arch. Med. Res. (2007) [Pubmed]
  15. Defects in human methionine synthase in cblG patients. Gulati, S., Baker, P., Li, Y.N., Fowler, B., Kruger, W., Brody, L.C., Banerjee, R. Hum. Mol. Genet. (1996) [Pubmed]
  16. Implication of the folate-methionine metabolism pathways in susceptibility to follicular lymphomas. Niclot, S., Pruvot, Q., Besson, C., Savoy, D., Macintyre, E., Salles, G., Brousse, N., Varet, B., Landais, P., Taupin, P., Junien, C., Baudry-Bluteau, D. Blood (2006) [Pubmed]
  17. Methionine synthase (MTR) 2756 (A --> G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome. Bosco, P., Guéant-Rodriguez, R.M., Anello, G., Barone, C., Namour, F., Caraci, F., Romano, A., Romano, C., Guéant, J.L. Am. J. Med. Genet. A (2003) [Pubmed]
  18. Polymorphism of the methionine synthase gene : association with homocysteine metabolism and late-onset vascular diseases in the Japanese population. Morita, H., Kurihara, H., Sugiyama, T., Hamada, C., Kurihara, Y., Shindo, T., Oh-hashi, Y., Yazaki, Y. Arterioscler. Thromb. Vasc. Biol. (1999) [Pubmed]
  19. The prognostic significance of genetic polymorphisms (Methylenetetrahydrofolate Reductase C677T, Methionine Synthase A2756G, Thymidilate Synthase tandem repeat polymorphism) in multimodally treated oesophageal squamous cell carcinoma. Sarbia, M., Stahl, M., von Weyhern, C., Weirich, G., Pühringer-Oppermann, F. Br. J. Cancer (2006) [Pubmed]
  20. A polymorphism of the methionine synthase reductase gene increases chromosomal damage in peripheral lymphocytes in smokers. Ishikawa, H., Ishikawa, T., Miyatsu, Y., Kurihara, K., Fukao, A., Yokoyama, K. Mutat. Res. (2006) [Pubmed]
  21. Methionine and serine formation in control and mutant human cultured fibroblasts: evidence for methyl trapping and characterization of remethylation defects. Fowler, B., Whitehouse, C., Wenzel, F., Wraith, J.E. Pediatr. Res. (1997) [Pubmed]
  22. Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. Christensen, B., Arbour, L., Tran, P., Leclerc, D., Sabbaghian, N., Platt, R., Gilfix, B.M., Rosenblatt, D.S., Gravel, R.A., Forbes, P., Rozen, R. Am. J. Med. Genet. (1999) [Pubmed]
  23. Effects of polymorphisms of methionine synthase and methionine synthase reductase on total plasma homocysteine in the NHLBI Family Heart Study. Jacques, P.F., Bostom, A.G., Selhub, J., Rich, S., Ellison, R.C., Eckfeldt, J.H., Gravel, R.A., Rozen, R. Atherosclerosis (2003) [Pubmed]
  24. High-level multiplex genotyping of polymorphisms involved in folate or homocysteine metabolism by matrix-assisted laser desorption/ionization mass spectrometry. Meyer, K., Fredriksen, A., Ueland, P.M. Clin. Chem. (2004) [Pubmed]
  25. Electron transfer in human methionine synthase reductase studied by stopped-flow spectrophotometry. Wolthers, K.R., Scrutton, N.S. Biochemistry (2004) [Pubmed]
  26. Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase. Olteanu, H., Munson, T., Banerjee, R. Biochemistry (2002) [Pubmed]
  27. The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. Mosharov, E., Cranford, M.R., Banerjee, R. Biochemistry (2000) [Pubmed]
  28. Hepatic transmethylation and blood alcohol levels. Barak, A.J., Beckenhauer, H.C., Tuma, D.J. Alcohol Alcohol. (1991) [Pubmed]
  29. Molecular cloning, pharmacological characterization, and histochemical distribution of frog vasotocin and mesotocin receptors. Acharjee, S., Do-Rego, J.L., Oh, D.Y., Moon, J.S., Ahn, R.S., Lee, K., Bai, D.G., Vaudry, H., Kwon, H.B., Seong, J.Y. J. Mol. Endocrinol. (2004) [Pubmed]
  30. Defects in auxiliary redox proteins lead to functional methionine synthase deficiency. Gulati, S., Chen, Z., Brody, L.C., Rosenblatt, D.S., Banerjee, R. J. Biol. Chem. (1997) [Pubmed]
  31. The presence of a transsulfuration pathway in the lens: a new oxidative stress defense system. Persa, C., Pierce, A., Ma, Z., Kabil, O., Lou, M.F. Exp. Eye Res. (2004) [Pubmed]
  32. Polymorphisms in genes involved in folate metabolism as risk factors for oedematous severe childhood malnutrition: a hypothesis-generating study. Marshall, K.G., Howell, S., Badaloo, A.V., Reid, M., Farrall, M., Forrester, T., McKenzie, C.A. Annals of tropical paediatrics. (2006) [Pubmed]
  33. Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Skibola, C.F., Smith, M.T., Hubbard, A., Shane, B., Roberts, A.C., Law, G.R., Rollinson, S., Roman, E., Cartwright, R.A., Morgan, G.J. Blood (2002) [Pubmed]
  34. Polymorphisms in the reduced folate carrier, thymidylate synthase, or methionine synthase and risk of colon cancer. Ulrich, C.M., Curtin, K., Potter, J.D., Bigler, J., Caan, B., Slattery, M.L. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  35. Hepatic transmethylation reactions in micropigs with alcoholic liver disease. Villanueva, J.A., Halsted, C.H. Hepatology (2004) [Pubmed]
  36. Hyperhomocysteinemia is related to residual glomerular filtration and folate, but not to methylenetetrahydrofolate-reductase and methionine synthase polymorphisms, in supplemented end-stage renal disease patients undergoing hemodialysis. Anwar, W., Guéant, J.L., Abdelmouttaleb, I., Adjalla, C., Gérard, P., Lemoel, G., Erraess, N., Moutabarrek, A., Namour, F. Clin. Chem. Lab. Med. (2001) [Pubmed]
  37. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Friso, S., Choi, S.W., Girelli, D., Mason, J.B., Dolnikowski, G.G., Bagley, P.J., Olivieri, O., Jacques, P.F., Rosenberg, I.H., Corrocher, R., Selhub, J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  38. Accurate and rapid "multiplex heteroduplexing" method for genotyping key enzymes involved in folate/homocysteine metabolism. Barbaux, S., Kluijtmans, L.A., Whitehead, A.S. Clin. Chem. (2000) [Pubmed]
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