Genomes and Genes
5 methyltetrahydrofolate homocysteine s methyltransferase
Summary: An enzyme that catalyzes the formation of methionine by transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine. It requires a cobamide coenzyme. The enzyme can act on mono- or triglutamate derivatives. EC 126.96.36.199.
- Zhu H, Wicker N, Shaw G, Lammer E, Hendricks K, Suarez L, et al. Homocysteine remethylation enzyme polymorphisms and increased risks for neural tube defects. Mol Genet Metab. 2003;78:216-21 pubmed..These results did not appear to be influenced by maternal periconceptional folic acid intake. However,the sample size of this study was limited, and a larger population study is needed to pursue these initial observations. ..
- Sharp L, Little J. Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol. 2004;159:423-43 pubmed..Overall, the roles of folate-pathway genes, folate, and related dietary factors in colorectal neoplasia are complex. Research priorities are suggested. ..
- Gueant J, Guéant Rodriguez R, Anello G, Bosco P, Brunaud L, Romano C, et al. Genetic determinants of folate and vitamin B12 metabolism: a common pathway in neural tube defect and Down syndrome?. Clin Chem Lab Med. 2003;41:1473-7 pubmed..The distinct data produced in different geographical areas may be explained by differences in the nutritional environment and genetic characteristics of the populations. ..
- Wang X, Duarte N, Cai H, Adachi T, Sim A, Cranney G, et al. Relationship between total plasma homocysteine, polymorphisms of homocysteine metabolism related enzymes, risk factors and coronary artery disease in the Australian hospital-based population. Atherosclerosis. 1999;146:133-40 pubmed..The contributions to total plasma homocysteine levels of the common mutations of genes coding for the enzymes controlling homocysteine metabolism are modest. ..
- Kawakami K, Ruszkiewicz A, Bennett G, Moore J, Watanabe G, Iacopetta B. The folate pool in colorectal cancers is associated with DNA hypermethylation and with a polymorphism in methylenetetrahydrofolate reductase. Clin Cancer Res. 2003;9:5860-5 pubmed..FIs could serve as biochemical markers for the risk of developing this disease, as well as for the prediction of toxicity and efficacy of fluorouracil-based treatments. ..
- Chen J, Stampfer M, Ma J, Selhub J, Malinow M, Hennekens C, et al. Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of myocardial infarction. Atherosclerosis. 2001;154:667-72 pubmed..It was concluded that influence of the MS (D919G) polymorphism on the plasma tHcy and folate levels is at most moderate, but should be further investigated in other large prospective studies. ..
- Lincz L, Scorgie F, Kerridge I, Potts R, Spencer A, Enno A. Methionine synthase genetic polymorphism MS A2756G alters susceptibility to follicular but not diffuse large B-cell non-Hodgkin's lymphoma or multiple myeloma. Br J Haematol. 2003;120:1051-4 pubmed..4-fold lower risk of follicular (odds ratio = 0.41, 95% confidence interval: 0.19-0.88, p = 0.02) but not diffuse large B-cell lymphoma. MM patients showed no significant difference in the polymorphisms compared with control subjects. ..
- De Marco P, Calevo M, Moroni A, Arata L, Merello E, Finnell R, et al. Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population. J Hum Genet. 2002;47:319-24 pubmed..This study shows that the MTHFRA1298C polymorphism is a genetic determinant for NTD risk in Italy. No association between the MSA2756G and NTD susceptibility was found. ..
- Yates Z, Lucock M. Interaction between common folate polymorphisms and B-vitamin nutritional status modulates homocysteine and risk for a thrombotic event. Mol Genet Metab. 2003;79:201-13 pubmed
- Zeh M, Leggewie G, Hoefgen R, Hesse H. Cloning and characterization of a cDNA encoding a cobalamin-independent methionine synthase from potato (Solanum tuberosum L.). Plant Mol Biol. 2002;48:255-65 pubmed..This experiment confirmed the presence of a day/night rhythm. Methionine synthase expression is regulated by photoassimilates but this seems not to detectably alter protein levels...
- Klerk M, Lievers K, Kluijtmans L, Blom H, den Heijer M, Schouten E, et al. The 2756A>G variant in the gene encoding methionine synthase: its relation with plasma homocysteine levels and risk of coronary heart disease in a Dutch case-control study. Thromb Res. 2003;110:87-91 pubmed..Before putting effort in additional epidemiological studies, it needs to be established first whether this polymorphism has functional consequences for enzyme activity. ..
- Silaste M, Rantala M, Sämpi M, Alfthan G, Aro A, Kesaniemi Y. Polymorphisms of key enzymes in homocysteine metabolism affect diet responsiveness of plasma homocysteine in healthy women. J Nutr. 2001;131:2643-7 pubmed..The 844ins68 of CBS gene did not affect plasma tHcy concentrations or diet responsiveness. In conclusion, diet responsiveness of plasma homocysteine may be genetically regulated. ..
- Song K, Song J, Choi J, Kim H, Shin J, Kim J. Homozygous VN (677C to T) and d/D (2756G to A) variants in the methylenetetrahydrofolate and methionine synthase genes in a case of hyperhomocysteinemia with stroke at young age. Exp Mol Med. 2001;33:106-9 pubmed..We report here on a case of occlusive stroke at young age and hyperhomocysteinemia with homozygous VN (677C to T) variant in the MTHFR gene as well as homozygous D/D (2756G to A) variant in the MS gene. ..
- Leclerc D, Campeau E, Goyette P, Adjalla C, Christensen B, Ross M, et al. Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Hum Mol Genet. 1996;5:1867-74 pubmed..We discuss the possibility that a mild deficiency of methionine synthase activity could be associated with mild hyperhomocysteinemia, a risk factor for cardiovascular disease and possibly neural tube defects. ..
- Matsuo K, Suzuki R, Hamajima N, Ogura M, Kagami Y, Taji H, et al. Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant lymphoma. Blood. 2001;97:3205-9 pubmed..Further studies to confirm the association and detailed biologic mechanisms are now required. ..
- Tsai M, Bignell M, Yang F, Welge B, Graham K, Hanson N. Polygenic influence on plasma homocysteine: association of two prevalent mutations, the 844ins68 of cystathionine beta-synthase and A(2756)G of methionine synthase, with lowered plasma homocysteine levels. Atherosclerosis. 2000;149:131-7 pubmed
- Zhang G, Dai C. Gene polymorphisms of homocysteine metabolism-related enzymes in Chinese patients with occlusive coronary artery or cerebral vascular diseases. Thromb Res. 2001;104:187-95 pubmed..However, CBS 844ins68 may be a protective factor against vascular thromboembolic disease. The prevalence of CBS 844ins68 and MS A2756G in Chinese population is obviously lower than in Western Caucasian population. ..
- Goode E, Potter J, Bigler J, Ulrich C. Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev. 2004;13:157-62 pubmed..These findings add to what is known about the complexities of genetic variations in one-carbon-metabolizing enzymes in relation to colorectal carcinogenesis. ..
- Tsai M, Welge B, Hanson N, Bignell M, Vessey J, Schwichtenberg K, et al. Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases. Atherosclerosis. 1999;143:163-70 pubmed
- Leclerc D, Wilson A, Dumas R, Gafuik C, Song D, Watkins D, et al. Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria. Proc Natl Acad Sci U S A. 1998;95:3059-64 pubmed..The cloning of the cDNA will permit the diagnostic characterization of cblE patients and investigation of the potential role of polymorphisms of this enzyme as a risk factor in hyperhomocysteinemia-linked vascular disease...
- Banerjee R, Matthews R. Cobalamin-dependent methionine synthase. FASEB J. 1990;4:1450-9 pubmed..The review emphasizes the mechanistic information that will be needed in order to design rational inhibitors of the enzyme. ..
- Gemmati D, Ongaro A, Scapoli G, Della Porta M, Tognazzo S, Serino M, et al. Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin's lymphoma in adults. Cancer Epidemiol Biomarkers Prev. 2004;13:787-94 pubmed..These data are in accordance with the hypothesis that polymorphisms in the genes for folate and methionine metabolism might play a greater role in the occurrence of ALL than NHL by influencing DNA synthesis and/or DNA methylation. ..
- Olteanu H, Banerjee R. Redundancy in the pathway for redox regulation of mammalian methionine synthase: reductive activation by the dual flavoprotein, novel reductase 1. J Biol Chem. 2003;278:38310-4 pubmed
- Matsuo K, Ito H, Wakai K, Hirose K, Saito T, Suzuki T, et al. One-carbon metabolism related gene polymorphisms interact with alcohol drinking to influence the risk of colorectal cancer in Japan. Carcinogenesis. 2005;26:2164-71 pubmed..In conclusion, we found consistently significant interactions between one-carbon metabolism-related polymorphisms and alcohol drinking. ..
- Semmler A, Simon M, Moskau S, Linnebank M. The methionine synthase polymorphism c.2756A>G alters susceptibility to glioblastoma multiforme. Cancer Epidemiol Biomarkers Prev. 2006;15:2314-6 pubmed..72/0.26/0.02 and controls AA/AG/GG: 0.57/0.38/0.05, degrees of freedom = 2; chi(2) = 17.86 (Pearson); P < 0.001]. No association between glioblastoma multiforme and the two other polymorphisms was observed. ..
- Strong W, Schirch V. In vitro conversion of formate to serine: effect of tetrahydropteroylpolyglutamates and serine hydroxymethyltransferase on the rate of 10-formyltetrahydrofolate synthetase. Biochemistry. 1989;28:9430-9 pubmed..The in vivo concentrations of serine hydroxymethyltransferase and C1-tetrahydrofolate synthase in rabbit liver were determined. ..
- Kahleová R, Palyzová D, Zvara K, Zvarova J, Hrach K, Nováková I, et al. Essential hypertension in adolescents: association with insulin resistance and with metabolism of homocysteine and vitamins. Am J Hypertens. 2002;15:857-64 pubmed..These data suggest that hypertension in young individuals may be a part of early manifestation of insulin resistance syndrome, and that disturbed folate and homocysteine metabolism may play a role in the early stages of hypertension. ..
- Solanky N, Requena Jimenez A, D Souza S, Sibley C, Glazier J. Expression of folate transporters in human placenta and implications for homocysteine metabolism. Placenta. 2010;31:134-43 pubmed publisher..These data support the concept that placental folate transport is established early in pregnancy, providing folate for utilisation in placental Hcy metabolism. ..
- Tong S, Lee J, Song E, Lee K, Kim M, Yun Y, et al. The effects of polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) on the risk of cervical intraepithelial neoplasia and cervical cancer in Korean women. Cancer Causes Control. 2010;21:23-30 pubmed publisher..In addition, there was no significant association of MTHFR haplotypes with risk of CIN2/3 and cervical cancer. ..
- Artifoni L, Benetti E, Centi S, Negrisolo S, Ghiggeri G, Ginevri F, et al. The impact of eNOS, MTR and MTHFR polymorphisms on renal graft survival in children and young adults. Nephrol Dial Transplant. 2009;24:2931-7 pubmed publisher..0093, respectively). The association between eNOS 894G>T polymorphism of donors and graft survival seems to suggest a role for this gene in chronic allograft injury; however, further studies are needed to confirm this hypothesis. ..
- Suzuki T, Matsuo K, Hasegawa Y, Hiraki A, Wakai K, Hirose K, et al. One-carbon metabolism-related gene polymorphisms and risk of head and neck squamous cell carcinoma: case-control study. Cancer Sci. 2007;98:1439-46 pubmed..04), MTR A2756G (P = 0.04) and MTRR A66G (P = 0.03) polymorphisms. The results suggest that there may be interactions between one-carbon metabolism-related polymorphisms and alcohol drinking for HNSCC risk. ..
- Lawrance A, Deng L, Brody L, Finnell R, Shane B, Rozen R. Genetic and nutritional deficiencies in folate metabolism influence tumorigenicity in Apcmin/+ mice. J Nutr Biochem. 2007;18:305-12 pubmed
- Zhu W, Cheng J, Dao J, Zhao R, Yan L, Li S, et al. Polymorphism of methionine synthase gene in nuclear families of congenital heart disease. Biomed Environ Sci. 2004;17:57-64 pubmed..26 (95% CI: 0.11-0.60). MS gene variation in parents is associated with occurrence of CHD in offspring, and mutation allele (+) in parents may be related with the decrease of CHD risk in offspring. ..
- Chatterjee J, Miyamoto C, Zouzoulas A, Lang B, Skouris N, Meighen E. MetR and CRP bind to the Vibrio harveyi lux promoters and regulate luminescence. Mol Microbiol. 2002;46:101-11 pubmed
- Mora D, Parini C, Fortina M, Manachini P. Multilocus hybridization typing in Pediococcus acidilactici strains. Curr Microbiol. 2002;44:77-80 pubmed..acidilactici strains in five distinct genotypes according to the grouping previously obtained confirming that pediocin AcH/PA-1 producer strains represent one genomic lineage within the species P. acidilactici. ..
- Wilson A, Platt R, Wu Q, Leclerc D, Christensen B, Yang H, et al. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab. 1999;67:317-23 pubmed..Investigation of this polymorphism in other disorders associated with altered homocysteine metabolism, such as vascular disease, is clearly warranted. ..
- Parmeggiani F, Gemmati D, Costagliola C, Semeraro F, D Angelo S, Perri P, et al. Impact of coagulation-balance gene predictors on efficacy of photodynamic therapy for choroidal neovascularization in pathologic myopia. Ophthalmology. 2010;117:517-23 pubmed publisher..These findings document the presence of pharmacogenetic correlations between common coagulation-balance gene polymorphisms and different CNV responsiveness to PDT-V in Caucasian patients with neovascular PM. ..
- Wang M, Zhu H, Fu G, Wang M, Zhang Z, Lu Q, et al. Polymorphisms of methylenetetrahydrofolate reductase and methionine synthase genes and bladder cancer risk: a case-control study with meta-analysis. Clin Exp Med. 2009;9:9-19 pubmed publisher..71, 95% CI = 1.03-2.83). A meta-analysis of seven studies did not show a significant risk of bladder cancer in the MTHFR polymorphisms. The MTHFR polymorphisms and their haplotypes appear to jointly contribute to risk of bladder cancer. ..
- Zhao H, Li X, Zhang Z, Bi X, Wang B, Zhang J. Association analysis of methionine synthase gene 2756 A>G polymorphism and Alzheimer disease in a Chinese population. Brain Res. 2008;1204:118-22 pubmed publisher..690, 95% CI 0.884-3.232, p=0.110). Our data did not reveal significant association between the MS 2756 A>G polymorphism and AD development. However, a weak effect of the A allele on developing AD could not be completely excluded. ..
- Graulet B, Matte J, Desrochers A, Doepel L, Palin M, Girard C. Effects of dietary supplements of folic acid and vitamin B12 on metabolism of dairy cows in early lactation. J Dairy Sci. 2007;90:3442-55 pubmed
- Matsuo K, Hamajima N, Suzuki R, Ogura M, Kagami Y, Taji H, et al. Methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms and reduced risk of malignant lymphoma. Am J Hematol. 2004;77:351-7 pubmed..Lack of association with MTR polymorphism was also confirmed. ..
- Sreenivasulu N, Altschmied L, Panitz R, Hähnel U, Michalek W, Weschke W, et al. Identification of genes specifically expressed in maternal and filial tissues of barley caryopses: a cDNA array analysis. Mol Genet Genomics. 2002;266:758-67 pubmed..This gene, represented by clone HY09L21, may play a central role in transport processes and thus in embryo growth. ..
- Bandarian V, Matthews R. Measurement of energetics of conformational change in cobalamin-dependent methionine synthase. Methods Enzymol. 2004;380:152-69 pubmed
- Ulvik A, Vollset S, Hansen S, Gislefoss R, Jellum E, Ueland P. Colorectal cancer and the methylenetetrahydrofolate reductase 677C -> T and methionine synthase 2756A -> G polymorphisms: a study of 2,168 case-control pairs from the JANUS cohort. Cancer Epidemiol Biomarkers Prev. 2004;13:2175-80 pubmed..In summary, we found significantly reduced risk of colorectal cancer in subjects with the MTHFR 677 TT and MTR 2756 GG genotypes. No interaction between the polymorphisms, or of either polymorphism with tHcy, was detected. ..
- Croft M, Lawrence A, Raux Deery E, Warren M, Smith A. Algae acquire vitamin B12 through a symbiotic relationship with bacteria. Nature. 2005;438:90-3 pubmed..The source of cobalamin seems to be bacteria, indicating an important and unsuspected symbiosis. ..
- Sarbia M, Stahl M, von Weyhern C, Weirich G, Pühringer Oppermann F. The prognostic significance of genetic polymorphisms (Methylenetetrahydrofolate Reductase C677T, Methionine Synthase A2756G, Thymidilate Synthase tandem repeat polymorphism) in multimodally treated oesophageal squamous cell carcinoma. Br J Cancer. 2006;94:203-7 pubmed..Determination of MTHFR C677T and TS tandem repeat polymorphism has no predictive value...
- Ubeda N, Alonso Aperte E, Varela Moreiras G. Acute valproate administration impairs methionine metabolism in rats. J Nutr. 2002;132:2737-42 pubmed..The acute effects of VPA suggest that the alterations in the methionine cycle could be the common mechanism underlying the hepatotoxic, teratogenic and antifolate effects of the drug. ..
- Zheng D, Yan L, Birke R. Electrochemical and spectral studies of the reactions of aquocobalamin with nitric oxide and nitrite ion. Inorg Chem. 2002;41:2548-55 pubmed..These results can be used to explain a number of physiological effects involving NO interaction in biological systems with added cobalamin or with cobalamin in the methionine synthase enzyme. ..
- Matthews J. The cytotoxic effect of the vitamin B12 inhibitor cyanocobalamin [c-lactam], and a review of other vitamin B12 antagonists. Leuk Lymphoma. 1998;31:21-37 pubmed..We hypothesize that impaired DNA synthesis in vitamin B12 deficiency is the result of diverting serine away from thymidylate synthesis, into homocysteine metabolism. ..
- Ouerhani S, Rouissi K, Marrakchi R, Ben Slama M, Sfaxi M, Chebil M, et al. Combined effect of NAT2, MTR and MTHFR genotypes and tobacco on bladder cancer susceptibility in Tunisian population. Cancer Detect Prev. 2009;32:395-402 pubmed..Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are enzymes that play central roles in the folate metabolic pathway. The MTHFR 677*T and MTR 2756*G variants are associated with decreased enzyme activity...
- Araki H, Fukushima M, Kamiyama Y, Shirasaka T. Effect of consecutive lower-dose cisplatin in enhancement of 5-fluorouracil cytotoxicity in experimental tumor cells in vivo. Cancer Lett. 2000;160:185-91 pubmed..Consecutive lower-dose CDDP also may be concluded to act as an important modulator of the enhancement of 5-FU cytotoxicity in experimental tumors. ..
- Membrillo Hernandez J, Coopamah M, Channa A, Hughes M, Poole R. A novel mechanism for upregulation of the Escherichia coli K-12 hmp (flavohaemoglobin) gene by the 'NO releaser', S-nitrosoglutathione: nitrosation of homocysteine and modulation of MetR binding to the glyA-hmp intergenic region. Mol Microbiol. 1998;29:1101-12 pubmed..As GSNO and SNP upregulate hmp similarly, the NO released in the former case on reaction with homocysteine cannot be involved in hmp regulation. ..
- Chiang Y, Ge X, Chou C, Wu W, Chiang T. Nucleotide sequence diversity at the methionine synthase locus in endangered Dunnia sinensis (Rubiaceae): an evaluation of the positive selection hypothesis. Mol Biol Evol. 2002;19:1367-75 pubmed
- Brosnan J, Wijekoon E, Warford Woolgar L, Trottier N, Brosnan M, Brunton J, et al. Creatine synthesis is a major metabolic process in neonatal piglets and has important implications for amino acid metabolism and methyl balance. J Nutr. 2009;139:1292-7 pubmed publisher..Creatine synthesis is a quantitatively major metabolic process in piglets. ..
- Roeder S, Dreschler K, Wirtz M, Cristescu S, van Harren F, Hell R, et al. SAM levels, gene expression of SAM synthetase, methionine synthase and ACC oxidase, and ethylene emission from N. suaveolens flowers. Plant Mol Biol. 2009;70:535-46 pubmed publisher..suaveolens flowers. It is emitted in a burst at the end of the life span of the flowers, which correlates with the increased expression of the 1-aminocyclopropane-1-carboxylate oxidase (NsACO). ..
- Zhang G, Dai C. [Correlation analysis between plasma homocysteine level and polymorphism of homocysteine metabolism related enzymes in ischemic cerebrovascular or cardiovascular diseases]. Zhonghua Xue Ye Xue Za Zhi. 2002;23:126-9 pubmed..Hyperhomocysteinemia is an important risk factor for ischemic cerebrovascular and cardiovascular disease. The homozygosity of MTHFR C677T may contribute to the increase of plasma Hcy and vascular damage. ..
- Luschinsky C, Drummond J, Matthews R, Ludwig M. Crystallization and preliminary X-ray diffraction studies of the cobalamin-binding domain of methionine synthase from Escherichia coli. J Mol Biol. 1992;225:557-60 pubmed..9 A, b = 55.4 A, c = 103.8 A. For two molecules per asymmetric unit, the calculated VM value is 2.45 A3/Da. A native data set has been collected to 3 A resolution. ..
- Adjalla C, Amouzou E, Sanni A, Abdelmouttaleb I, Chabi N, Namour F, et al. Low frequency of mutated methylenetetrahydrofolate reductase 677C-->T and 1298A-->C genetics single nucleotide polymorphisms (SNPs) in Sub-Saharan populations. Clin Chem Lab Med. 2003;41:1028-32 pubmed..The 677TT low frequency may be related to the high effect of this mutation on homocysteine metabolism in the environmental conditions of this African region. ..
- Lissowska J, Gaudet M, Brinton L, Chanock S, Peplonska B, Welch R, et al. Genetic polymorphisms in the one-carbon metabolism pathway and breast cancer risk: a population-based case-control study and meta-analyses. Int J Cancer. 2007;120:2696-703 pubmed..In conclusion, this report does not support a substantial overall association between the evaluated polymorphisms in the one-carbon metabolism pathway and breast cancer risk. ..
- Yu K, Zhang J, Zhang J, Dou C, Gu S, Xie Y, et al. Methionine synthase A2756G polymorphism and cancer risk: a meta-analysis. Eur J Hum Genet. 2010;18:370-8 pubmed publisher..Large-scale, well-designed, and population-based studies are required to further investigate gene-gene and gene-environment interactions on MTR A2756G polymorphism and tissue-specific cancer risk in an ethnicity-specific population. ..
- Blasco C, Caballeria J, Deulofeu R, Lligoña A, Pares A, Lluis J, et al. Prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics. Alcohol Clin Exp Res. 2005;29:1044-8 pubmed