Disease relevance of MTRR

• In conclusion, genetic determinants affecting the cellular availability or MTRR-dependent reduction of B12 may increase the risk of spina bifida [1].
• 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) [2].
• 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 [3].
• At the same time, micronucleus data indicate that the MTRR 66GG variant may represent another individual trait of relative genomic instability, thus supporting epidemiological data on increased risk of Down syndrome conception in MTRR 66GG subjects [4].
• CONCLUSIONS: By analysis of a large number of subjects and a more specific patient selection, we showed the first genetic evidence that MTHFR C677T, MS A2756G and MTRR A66G genotypes were independently associated with male infertility [5].

Psychiatry related information on MTRR

• 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].
• We did not find significant interactions between polymorphisms in MTHFR, MTR, and MTRR genes and dietary folate and alcohol consumption [7].
• Therefore expressing intensity as a percentage of MSR for sub-maximal and maximal velocities and as a percentage of AnSR for supra-maximal velocities allows individual differences in anaerobic work capacity to be taken into account and running times to exhaustion to be predicted accurately [8].
• Eight HIV-1-infected methadone patients with impaired neuropsychological test performance participated in an inpatient double-blind placebo-controlled crossover trial of MSR 20-40 mg/day [9].

High impact information on MTRR

• Escherichia coli MS, however, was not activated by hMSR [10].
• 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 [10].
• Analysis of data on variants of two genes involved in homocysteine remethylation/methionine biosynthesis--methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G--provided evidence that both variants influence the risk of spina bifida via the maternal rather than the embryonic genotype [11].
• In the present report, we asked whether variation at MTHFR (677C-->T) or MTRR (66A-->G) might be associated with human trisomies other than trisomy 21 [12].
• Methionine synthase reductase (MTRR) is another enzyme essential for normal folate metabolism [13].

Chemical compound and disease context of MTRR

• 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 [3].
• MSR and its individual flavin-binding domains were cloned as GST-tagged fusion proteins for expression and purification from Escherichia coli [14].

Biological context of MTRR

• The prevalence of the MTRR AA, AG, GG genotypes was 19, 50 and 31%, respectively [15].
• Recent evidence has suggested that 5,10-methylenetetrahydrofolate reductase (MTHFR) and/or methionine synthase reductase (MTRR) might contribute to the maternal risk of trisomy 21 [16].
• The gene MTRR has been localized to chromosome 5p15.2-15 [17].
• Therefore, studies on human genotoxicity based on cytogenetic markers of MN should take into account both the MTRR polymorphism and the potential confounding effect of smoking, although these preliminary findings need to be validated in larger populations because of the relatively small sample size [18].
• The insertion is caused by a T>C transition within intron 6 of the MTRR gene, which presumably leads to activation of an exon splicing enhancer [19].

Anatomical context of MTRR

• Methylenetetrahydrofolate reductase (MTHFR) 677C>T and methionine synthase reductase (MTRR) 66A>G polymorphisms: association with serum homocysteine and angiographic coronary artery disease in the era of flour products fortified with folic acid [15].
• Importantly, transfection of fibroblasts of cblE patients with a wild-type MTRR minigene expression construct resulted in a significant approximately four-fold increase of methionine synthesis, indicating correction of the enzyme defect [20].
• High MSRA mRNA and protein levels as well as MSR activity were found in cultured human keratinocytes [21].
• Mitral valve leaflets were smooth and white in a patients without mitral valvular disease, while the leaflets were yellow, thick and irregular, and blood regurgitation from the left ventricle into the left atrium could be observed in two patients with rheumatic MSR [22].

Associations of MTRR with chemical compounds

• In conclusion, polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are related to MTX resistance in pediatric patients with ALL [23].
• On multivariate analysis, the MTRR genotypes were not associated with serum homocysteine or with significant CAD [15].
• The methionine synthase reductase gene (MTRR) mutation is an A to G substitution, 66A-->G, that converts an isoleucine to a methionine residue [24].
• In the presence of MSR and NADPH, holoenzyme formation from apoMS and methylcobalamin was significantly enhanced [10].
• A common MTRR polymorphism, i.e. a 66 A-->G substitution specifying an isoleucine to methionine substitution (I22M), was recently identified [25].

Physical interactions of MTRR

• 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 [26].

Enzymatic interactions of MTRR

• Methionine synthase reductase (MSR) catalyzes the conversion of the inactive form of human methionine synthase to the active state of the enzyme [27].
• Human methionine synthase reductase (MSR) catalyzes the NADPH-dependent reductive methylation of methionine synthase [14].

Other interactions of MTRR

• Patients with the MTHFR 1298AC variant or the MTRR 66 G-allele showed decreased in vitro MTX sensitivity measured under both test conditions [23].
• Moreover, after correction for age, gender and GSTM1 genotype, a significant association (P = 0.026) between the MTRR 66GG variant genotype and higher micronucleus rates was observed [4].
• Investigations also showed that purified recombinant human methionine synthase reductase (MSR) in combination with purified ATR can convert cob(II)alamin to AdoCbl in vitro [28].
• Four genetic polymorphisms-MTHFR C677T and A1298C, MTRR A66G, and ALDH2 Glu487Lys-were determined using blood samples [29].
• Our preliminary findings suggest no association between the MTRR A66G and MTHFR A1298C polymorphisms and MS [30].

Analytical, diagnostic and therapeutic context of MTRR

• 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 [3].
• CONCLUSION: This study does not support the routine use of MTHFR or MTRR genotyping for prognostic evaluation or risk-stratification in kidney transplant recipients [31].
• Effects of single-nucleotide polymorphisms in MTHFR and MTRR on mortality and allograft loss in kidney transplant recipients [31].
• The meta-analyses demonstrated that the maternal MTRR 66GG genotype was associated with an overall 55% (95% CI 1.04-2.30) increase in NTD risk and that the MTRR 66GG genotype did not increase NTD risk in children (OR 0.96, 95% CI 0.46-2.01) [32].
• We examined two mutations in MTRR in a cross-sectional study of 733 kidney graft recipients [33].

References