Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methylenetetrahydrofolate reductase (MR) deficiency is the most common inborn error of folate metabolism with more than two dozen patients described. The phenotypic spectrum ranges from severe neurological deterioration and early death to asymptomatic adults. Some patients with a severe deficiency of MR have been shown to have thermolabile reductase at 55 degrees C. Since methyltetrahydrofolate, the product of MR, is a methyl donor for methylcobalamin (MeCbl), the cofactor for methionine synthase (MS), we have looked at MeCbl accumulation and MS activity in fibroblasts from 15 patients with MR deficiency. Thermolabile MR was most often but not always seen in later onset disease. MeCbl levels were often lowest in the patients with early onset disease. All but two patients had levels of methionine synthase within the control range.
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PMID:Methylenetetrahydrofolate reductase (MR) deficiency: thermolability of residual MR activity, methionine synthase activity, and methylcobalamin levels in cultured fibroblasts. 162 52

Methylenetetrahydrofolate reductase in Clostridium formicoaceticum has been purified to a specific activity of 140 mumol min-1 mg-1 when assayed at 37 degrees C, pH 7.2, in the direction of oxidation of 5-methyltetrahydrofolate with benzyl viologen as electron acceptor. The purified enzyme is judged to be homogeneous by polyacrylamide disc-gel electrophoresis and gel filtration. The enzyme which is an octamer has a molecular weight of about 237,000 and consists of four each of two different subunits having the molecular weights 26,000 and 35,000. The octameric enzyme contains per mol 15.2 +/- 0.3 iron, 2.3 +/- 0.2 zinc, 19.5 +/- 1.3 acid-labile sulfur, and 1.7 FAD. The UV-visible absorbance spectrum has a peak at 385 nm and a shoulder at 430 nm and is that of a flavoprotein containing iron-sulfur centers. The reductase, which is sensitive to oxygen, must be handled anaerobically and is stabilized by 2 mM dithionite. It catalyzes the reduction of methylene blue, menadione, benzyl viologen, rubredoxin, and FAD with 5-methyltetrahydrofolate and the oxidation of reduced ferredoxin and FADH2 with 5,10-methylenetetrahydrofolate. No activity was observed with pyridine nucleotides. It is suggested that the physiologically important reaction catalyzed by the enzyme is the reduced ferredoxin-dependent reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.
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PMID:Purification and properties of 5,10-methylenetetrahydrofolate reductase, an iron-sulfur flavoprotein from Clostridium formicoaceticum. 638 90

Pig liver methylenetetrahydrofolate reductase catalyzes the reduction of quinonoid dihydropterins in vitro. Either NADPH or methyltetrahydrofolate can serve as the electron donor. Methylenetetrahydrofolate reductase can also suppor phenylalanine hydroxylation in vitro by regeneration of the tetrahydropterin cofactor. These results lend support to the proposal that reduction of methylenetetrahydrofolate proceeds by tautomerization of the 5-iminium cation to form quinonoid 5-methyldihydrofolate, which is then reduced to methyltetrahydrofolate (Matthews, R. G., and Haywood, B. J. (1979) Biochemistry 18, 4845-4851). Under Vmax conditions, the turnover numbers for the NADPH-linked reductions of the quinonoid forms of 6,7-dimethyldihydropterin, dihydrobiopterin, and dihydrofolate are all about the same as that for the reduction of methylenetetrahydrofolate. The Km values for racemic mixtures of the same quinonoid acceptors are 40, 30, and 20 microM, respectively, while the Km for (6R,S)methylenetetrahydrofolate is 20 microM at pH 7.2 in phosphate buffer. The reduction of quinonoid dihydropterins is inhibited by adenosylmethionine and dihydropteroylhexaglutamate, which are known to modulate methylenetretrahydrofolate reductase activity.
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PMID:Characterization of the dihydropterin reductase activity of pig liver methylenetetrahydrofolate reductase. 696 65

Methylenetetrahydrofolate reductase catalyzes the reduction of methylenetetrahydrofolate to methyltetrahydrofolate. This reaction commits one carbon units to the pathways of adenosylmethionine-dependent methylation in mammalian cells. We have purified the pig liver enzyme to homogeneity and shown that it contains FAD as a non-covalently bound prosthetic group. Methylenetetrahydrofolate is not only a substrate for the reductase, but also for thymidylate synthase and for methylenetetrahydrofolate dehydrogenase. The latter reaction leads to utilization of one carbon units in de novo purine biosynthesis. A priori, one might expect that methylenetetrahydrofolate reductase activity would be modulated by cellular requirements for de novo biosynthesis of purines and pyrimidines, as well as by cellular levels of adenosylmethionine. Methylenetetrahydrofolate reductase is inhibited by dihydrofolate and its polyglutamate analogues. The Ki is 6.5 microM for dihydrofolate and decreases with each additional glutamyl residue to a minimum value of 0.013 microM for dihydropteroylhexaglutamate. The I50 for dihydropteroylhexaglutamate inhibition of reductase activity in the presence of 0.5 microM methylenetetrahydropteroylhexaglutamate is 0.07 microM. We propose that stimulation of thymidylate synthase activity (as in the replicating cell) may lead to elevations in the steady state levels of cellular dihydrofolate derivatives and to resultant inhibition of methylenetetrahydrofolate reductase activity. Thus methylenetetrahydrofolate derivatives would be spared for purine and pyrimidine biosynthesis. We have also examined the inhibition of methylenetetrahydrofolate reductase by adenosylmethionine, which serves as an allosteric effector of the enzymatic activity. Adenosylmethionine induces a slow transition in the enzyme, and leads to the inhibition of NADPH-menadione, NADPH-methylenetetrahydrofolate and methyltetrahydrofolate-menadione oxido-reductase activities.
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PMID:Modulation of methylenetetrahydrofolate reductase activity by S-adenosylmethionine and by dihydrofolate and its polyglutamate analogues. 705 69

To evaluate whether increased plasma homocysteine concentrations (hyperhomocysteinemia) are associated with thrombosis of arteriovenous (AV) grafts, we determined plasma homocysteine, plasma and erythrocyte folate, plasma vitamin B12, and vitamin B6 (pyridoxal-5'-phosphate [PLP]) in 48 patients (45 black patients and three white patients) with end-stage renal disease who received hemodialysis. 5,10-Methylenetetrahydrofolate reductase (MTHFR) genotypes were also analyzed. The patients were divided into two groups, including a thrombosis-prone group with frequent graft loss (n = 24) and a control group with prolonged graft survival who were matched by age and duration of dialysis (n = 24). Hyperhomocysteinemia (>15 micromol/L) was found in 42 patients. There were no significant differences in all values, including the concentrations of homocysteine and vitamins between the two groups. Based on plasma folate and PLP concentrations, over 70% of patients appeared to have inadequate folate and/or vitamin B6 nutriture. Plasma homocysteine concentrations showed significant negative correlations with plasma and erythrocyte folate, and plasma vitamin B12 in all patients combined, whereas no significant correlation was found between plasma PLP and homocysteine concentrations. Among 48 patients, the heterozygous mutation (Val/Ala) of MTHFR was found only in three patients, two of whom belonged to the thrombosis-prone group and one to the control group, and there were no individuals with homozygous thermolabile mutation (Val/Val). All three white patients had Ala/Ala genotype, and 3 in 45 black patients (6.7%) were heterozygotes (Val/Ala).
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PMID:Homocysteine, B vitamins, and vascular-access thrombosis in patients treated with hemodialysis. 974 Jan 65

5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism, has two common polymorphisms that affect enzyme activity. The objective of this study was to examine whether there was a correlation between the genotype or haplotype of the MTHFR gene and the efficacy or toxicity of methotrexate (MTX) in the treatment of rheumatoid arthritis. MTX-treated rheumatoid arthritis patients (n = 106) were selected from outpatient clinics and used for a retrospective study to examine the correlation between genotypes or haplotypes concerning polymorphisms of the MTHFR gene, and the efficacy or toxicity of MTX. Estimation of the haplotype frequencies was performed by maximum likelihood estimation based on expectation maximization algorithm. Single locus analysis examining each locus separately showed that patients with 1298C were receiving significantly lower doses of MTX compared to patients without [P < 0.05, relative risk (RR) = 2.18, 95% confidence interval (CI) 1.17-4.06], while a higher rate of overall MTX toxicity was observed in patients with 677T than those without (P < 0.05, RR = 1.25, 95% CI 1.05-1.49). An estimation of haplotype frequencies showed that there was no 677T-1298C haplotype in the population. Posterior distribution of the diplotype configuration for each individual was concentrated on a single configuration. Patients with the 677C-1298C haplotype were receiving lower doses of MTX than those without (P < 0.05, RR = 2.14, 95% CI 1.13-4.07), while subjects with 677T-1298A had a higher frequency of side-effects from MTX (P < 0.05, RR = 1.42, 95% CI 1.11-1.82). Both single locus and haplotype analyses suggest that polymorphisms within the MTHFR gene are associated with both the efficacy and toxicity of MTX in rheumatoid arthritis patients. Pharmacokinetic studies are necessary to prove the association.
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PMID:Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. 1192 32

5,10-Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism by channeling one-carbon units between nucleotide synthesis and methylation reactions. Severe enzyme deficiency leads to hyperhomocysteinemia and homocystinuria, with altered folate distribution and a phenotype that is characterized by damage to the nervous and vascular systems. Two frequent polymorphisms in the human MTHFR gene confer moderate functional impairment of MTHFR activity for homozygous mutant individuals. The C to T change at nucleotide position 677, whose functional consequences are dependent on folate status, has been extensively studied for its clinical consequences. A second polymorphism, an A to C change at nucleotide position 1298, is not as well characterized. Still equivocal are associations between MTHFR polymorphisms and vascular arteriosclerotic or thrombotic disease. Neural tube defects and pregnancy complications appear to be linked to impaired MTHFR function. Colonic cancer and acute leukemia, however, appear to be less frequent in individuals homozygous for the 677T polymorphism.MTHFR polymorphisms influence the homocysteine-lowering effect of folates and could modify the pharmacodynamics of antifolates and many other drugs whose metabolism, biochemical effects, or target structures require methylation reactions. However, only preliminary evidence exists for gene-drug interactions. This review summarizes the biochemical basis and clinical evidence for interactions between MTHFR polymorphisms and several disease entities, as well as potential interactions with drug therapies. Future investigations of MTHFR in disease should consider the influence of other variants of functionally-related genes as well as the medication regimen of the patients. Animal models for genetic deficiencies in folate metabolism will likely play a greater role in our understanding of folate-dependent disorders.
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PMID:Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences. 1208 67

5,10-Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are two of the key enzymes in the folate/vitamin B12-dependent remethylation of homocysteine to methionine. The frequencies of MTHFR single nucleotide polymorphisms (SNPs), 677C-->T, 1298A-->C, 1317T-->C and of MTR, 2756A-->G, have been widely studied in Caucasians, but they have never been reported simultaneously in a large population from Sub-Saharan Africa. Presently, we report the prevalence of these SNPs and their relationship to homocysteine in 240 subjects recruited in West Africa. The frequencies of the mutant genotypes 677TT (0.8%) and 1298CC (2%) were lower than that usually observed in Caucasians, while the frequency of the mutant 1317CC was higher (16%). We formed a systematic association of the mutated MTHFR 677C-->T SNP with a 1298A/1317T common haplotype. The MTHFR mutant genotype 677TT was associated with an intermediate hyperhomocysteinemia (92.4 +/- 6.0 micromol/l) higher than that described in Caucasians. The 2756A-->G SNP in the MTR was similarly distributed in Africans compared to Caucasians. In conclusion, the MTHFR 677TTor 1298CC genotypes are much rarer in Africans than in Caucasians. 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.
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PMID:Low frequency of mutated methylenetetrahydrofolate reductase 677C-->T and 1298A-->C genetics single nucleotide polymorphisms (SNPs) in Sub-Saharan populations. 1296 9

5,10-Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in the folate metabolic pathway. Common genetic polymorphisms in the human MTHFR gene are associated with individual variation in the efficacy and toxicity of chemotherapeutic agents, such as methotrexate and 5-fluorouracil. However, the full range of polymorphisms and intragene haplotypes in the human MTHFR gene remains unclear. Furthermore, cellular mechanisms by which common, naturally occurring nonsynonymous coding single nucleotide polymorphisms (cSNPs) might alter the function of this enzyme have not been defined. The present study focused on the systematic identification and investigation of common polymorphisms and haplotypes in the MTHFR gene using a genotype-to-phenotype strategy, followed by functional genomic studies. Specifically, we resequenced exons, splice junctions and portions of the 5'-flanking region (5'-FR) of the human MTHFR gene using 240 DNA samples from four ethnic groups. A total of 65 polymorphisms were observed, 11 of which were nonsynonymous cSNPs. We then performed functional genomic studies with constructs for wild-type and 15 variant allozymes (some with multiple alterations in amino acid sequence) using a mammalian expression system. Activity for the variant allozymes ranged from 13% to 149% of wild-type activity. Levels of immunoreactive protein for the allozymes ranged from 31% to 120% of wild-type and were significantly correlated with enzyme activity (Rp=0.85, P<0.0001), suggesting that a major mechanism by which nonsynonymous cSNPs influence the function of this gene is by alteration in the quantity of protein. These observations represent steps towards an understanding of molecular genetic mechanisms responsible for variation in MTHFR function that may contribute to individual differences in drug efficacy and toxicity, as well as disease risk.
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PMID:Human methylenetetrahydrofolate reductase pharmacogenomics: gene resequencing and functional genomics. 1653 73

Interictally, migraineurs have on average a reduction in habituation of pattern-reversal visual evoked potentials (PR-VEP) and in mitochondrial energy reserve. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and its C677T polymorphism may be more prevalent in migraine. The aim of this study was to search in migraineurs for a correlation between the MTHFR C677T polymorphism and the PR-VEP profile. PR-VEP were recorded in 52 genotyped migraine patients: 40 female, 24 without (MoA), 28 with aura (MA). Among them 21 had a normal genotype (CC), 18 were heterozygous (CT) and 13 homozygous (TT) for the MTHFR C677T polymorphism. Mean PR-VEP N1-P1 amplitude was significantly lower in CT compared with CC, and tended to be lower in TT with increasing age. The habituation deficit was significantly greater in CC compared with TT subjects. The correlation between the cortical preactivation level, as reflected by the VEP amplitude in the first block of averages, and habituation was stronger in CC than in CT or TT. The MTHFR C677T polymorphism could thus have an ambiguous role in migraine. On one hand, the better VEP habituation which is associated with its homozygosity, and possibly mediated by homocysteine derivatives increasing serotoninergic transmission, may protect the brain against overstimulation. On the other hand, MTHFR C677T homozygosity is linked to a reduction of grand average VEP amplitude with illness duration, which has been attributed to brain damage.
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PMID:Search for correlations between genotypes and electrophysiological patterns in migraine: the MTHFR C677T polymorphism and visual evoked potentials. 1771 93


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