Disease relevance of MTR

• Single nucleotide polymorphisms (SNPs) within the MTRR gene may potentially compromise MTR activity leading to elevated homocysteine levels, a known risk factor for neural tube defects (NTDs) [1].
• In conclusion, our data provide evidence supporting the association between the MTR 2756A>G and MTRR 66A>G polymorphisms and lung cancer risk, which may be modulated by dietary nutrient intake [2].
• Escherichia coli MS, however, was not activated by hMSR [3].
• The MS 2756 AG/GG genotypes were significantly under-represented in NHL (26.2%) vs control subjects (37.2%; P = 0.02), and conferred a 2.4-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 [4].
• By classifying 360 infertile patients into 174 azoospermia and 186 oligoasthenoteratozoospermia (OAT) subjects, the MTHFR 677TT and MS 2756GG types were significantly associated with the azoospermia group (P = 0.0227 and 0.0063, respectively) [5].

Psychiatry related information on MTR

• Finally, those with the MS 2756AG/GG and MTRR 66AG/GG genotypes revealed a 2.2-fold ALL risk reduction (OR 0.45, 95% CI 0.10-0.85) [6].
• Allele epsilon4 of the APO-E and IL-1B CC genotypes increased the risk of severe Alzheimer's disease associated with the MTR 2756 AA genotype by 3.3-fold and 1.5-fold, respectively [7].
• The possible association of the MTR polymorphism with lower risk of colorectal cancer especially among those with low alcohol consumption, in the same direction as for the MTHFR polymorphism, is intriguing [8].
• Association of IL-1 RN*2 allele and methionine synthase 2756 AA genotype with dementia severity of sporadic Alzheimer's disease [7].
• Methionine synthase deficiency is characterized by a megaloblastic anaemia occurring early in life that is more or less folate-responsive and associated with mental retardation [9].

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

• The MTR 2756AA genotype conferred a greater multivariate-adjusted relative risk of FL, and the risk was multiplied by almost 5 in the TYMS2R(-)/MTR 2756AA combination [16].
• In conclusion, our results provide evidences that homocysteine and MTR genetic polymorphism are two potent risk factors for mothers to have a DS child in Sicily [17].
• The methionine synthase genotype was analyzed by polymerase chain reaction followed by HaeIII digestion; allele frequencies for the D919G variant of the enzyme proved to be similar in all 3 subject groups (control subjects, 0.17; coronary artery disease patients, 0. 17; and ischemic stroke patients, 0.19) [18].
• A point mutation in the encoding region of the methionine synthase gene, which results in substitution of an aspartic acid for a glycine residue (D919G), has been identified in patients of the cblG genetic complementation group; these patients exhibit significantly decreased methionine synthase activity [18].
• The prognostic significance of genetic polymorphisms (Methylenetetrahydrofolate Reductase C677T, Methionine Synthase A2756G, Thymidilate Synthase tandem repeat polymorphism) in multimodally treated oesophageal squamous cell carcinoma [19].

Anatomical context of MTR

• A polymorphism of the methionine synthase reductase gene increases chromosomal damage in peripheral lymphocytes in smokers [20].
• Methionine synthase genetic polymorphism MS A2756G alters susceptibility to follicular but not diffuse large B-cell non-Hodgkin's lymphoma or multiple myeloma [4].
• Schirch in cultured fibroblasts and indicate that disturbed MS function due to a specific genetic disorder is associated with reduced serine formation in vitro, which reflects availability of reduced folate coenzymes [21].
• The correction of this defect by vitamin B12 alone, in cblC/D mutant cell lines, correlates well with the clinical response in the patients and fits in well with the idea that reduced availability of folate coenzymes occurs in functional MS deficiency, in agreement with the methyl trap hypothesis [21].
• Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects [22].

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

• Methionine synthase reductase (MSR) catalyzes the conversion of the inactive form of human methionine synthase to the active state of the enzyme [26].
• It suffers two major metabolic fates: transmethylation catalyzed by methionine synthase or betaine homocysteine methyl transferase and transsulfuration catalyzed by cystathionine beta-synthase leading to cystathionine [27].

Regulatory relationships of MTR

• Betaine-homocysteine methyltransferase was induced in this group to compensate for the MS inhibition and liver betaine was lowered reflecting this induction [28].
• V1a, V2 and OT antagonists inhibited MT-induced MTR activation but not VT-induced VTR activation [29].
• We demonstrate that the mammalian methionine synthase can be activated in an NADPH-dependent reaction and requires a minimum of two redox proteins [30].
• We have shown that oxidative stress of H2O2 could increase the flux of this transsulfuration pathway by committing more homocysteine to cysteine and glutathione production as H2O2 (0.1 mM) inhibited the remethylation enzyme of methionine synthase while concurrently activating the CBS enzyme [31].

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

• In a hospital-based, case-control study of 1,035 lung cancer cases and 1,148 controls of non-Hispanic whites, frequency matched by age, sex, ethnicity and smoking status, the MTR 2756A>G and MTRR 66A>G polymorphisms were genotyped [2].
• 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 [36].
• DNA was extracted from pretherapeutic tumour biopsies and was subsequently genotyped for common genetic polymorphisms of three genes (MTHFR C677T, MTR A2756G, TS tandem repeat polymorphism) involved in folate metabolism and potentially in sensitivity to 5-FU-based chemotherapy [19].
• A liquid chromatography/MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T/T) and 187 homozygous for the wild-type (C/C) MTHFR genotype [37].
• METHODS: Sequence-specific heteroduplex generators for each of the MTHFR and MS single nucleotide polymorphisms were generated by site-directed mutagenesis [38].

References