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Query: EC:1.5.7.1 (methylenetetrahydrofolate reductase)
 2,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Dihydrofolate and dihydropteroylpolyglutamates inhibit pig liver methylenetetrahydrofolate reductase. In all cases the inhibition is linearly competitive with respect to methylenetetrahydrofolate. The Ki values decrease with each additional glutamyl residue from one to six, from a value of 6.5 microM for dihydrofolate to 0.013 microM for dihydropteroylhexaglutamate. Dihydropteroylheptaglutamate has a Ki of 0.065 microM. These data indicate a free energy of binding of approximately 0.75 kcal/mol for each of the five terminal glutamyl residues in dihydropteroylhexaglutamate. Methylenetetrahydropteroylpolyglutamates are substrates for the enzyme, and the increased free energy of binding is reflected in increased values for Vmax/Km with polyglutamate substrates. Vmax is increased 1.76-fold on going from the mono- to the diglutamate substrate; additional glutamyl residues lead to decreases in Km values for methylenetetrahydropteroylpolyglutamates. Our results suggest that the in vivo activity of methylenetetrahydrofolate reductase may also be sensitive to fluctuations in the ratio of methylenetetrahydropteroylpolyglutamates to dihydropteroylpolyglutamates and that this ratio may be important in determining the relative fluxes of methylenetetrahydropteroylpolyglutamates into the pathways leading to thymidylate biosynthesis and methionine regeneration.
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PMID:Interactions of pig liver methylenetetrahydrofolate reductase with methylenetetrahydropteroylpolyglutamate substrates and with dihydropteroylpolyglutamate inhibitors. 699 Sep 70

Tetrahydrofolate (H4folate) derivatives are chemically analogous to tetrahydropterins and dihydroflavins, and like these compounds can be oxidized readily. The roles of pterin and flavin cofactors in biological oxidoreductions are well documented. However, with the exception of the reaction catalyzed by thymidylate synthase, explicit oxidoreductions of the H4folate cofactor do not occur in enzyme-catalyzed folate-dependent reactions. We have been studying methylenetetrahydrofolate reductase from pig liver. This enzyme catalyzes the reversible conversion of the exocyclic N5,N10-methylene substituent to an N5-methyl group. Our studies suggest that the detailed mechanism of this reduction of an exocyclic group involves the oxidoreduction of the tetrahydropterin ring system in a manner that is not apparent from the overall reaction stoichiometry. We suggest that such latent oxidoreductions of H4folate cofactors may also occur in other H4folate-dependent reactions, such as the reaction catalyzed by methionine synthase.
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PMID:Are the redox properties of tetrahydrofolate cofactors utilized in folate-dependent reactions? 704 35

The distribution of folylpolyglutamates in normal and methylenetetrahydrofolate reductase-deficient human fibroblasts cultured in medium containing folic acid or 5-methyltetrahydrofolic acid has been determined. Human fibroblasts concentrated these folates to higher levels than in the medium, an effect that was more pronounced with methyltetrahydrofolate as the folate source. Over 95% of the intracellular vitamin derivatives were polyglutamates of chain length 2 to 10. The major derivatives were hexaglutamates in cells cultured with folic acid and heptaglutamates in cells cultured with methyltetrahydrofolic acid. No significant differences were detected in the polyglutamate distribution between normal and methylenetetrahydrofolate reductase-deficient fibroblast. Excess medium methionine reduced cell growth rates and intracellular vitamin levels and changed the predominant polyglutamate in cells cultured with methyltetrahydrofolate from hepta- to hexaglutamate. No significant differences were seen between the overall folate polyglutamate distributions of different one-carbon folate pools of normal fibroblasts, although slight changes in the proportions of individual polyglutamate forms were detected in the different pools.
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PMID:Folate derivatives in human cells: studies on normal and 5,10-methylenetetrahydrofolate reductase-deficient fibroblasts. 704 95

The specific activities of four folate enzymes have been measured in livers from preterm infants (Group 1), full-term infants (Group 2), and from control subjects (Group 3). The four enzymes studied were methylene tetrahydrofolate reductase (EC 1.1.1.68), methionine synthetase (EC 2.1.1.13), methylenetetrahydrofolate dehydrogenase (EC 1.5.1.5), and glutamate formiminotransferase (EC 2.1.2.5). The specific activities for methylenetetrahydrofolate reductase were 6.62 +/- 0.51, 4.42 +/- 0.31, and 2.60 +/- 0.40 (nmoles formaldehyde/mg protein/h, mean +/- S.E.) for groups 1, 2 and 3, respectively. The specific activities for the three groups for methionine synthetase were 0.99 +/0 0.11, 0.64 +/- 0.06, and 0.42 +/- 0.05 (nmoles methionine/mg protein/h), mean +/- S.E.). The specific activities for the three groups for glutamine formiminotransferase were 84.1 +/-10.7, 108.6 +/-14.6, and 104.3 +/- 17.8 (nmoles methenyltetrahydrofolate/mg protein/min, mean +/- S.E.). The specific activities for the three groups for methylenetetrahydrofolate dehydrogenase were 0.16 +/- 0.03, 0.39 +/- 0.07, and 0.92 +/- 0.16 (nmoles methenyltetrahydrofolate/mg protein/min, mean +/- S.E.). During development, the specific activities of methylenetetrahydrofolate reductase and methionine synthetase decreased whereas the specific activity of methylenetetrahydrofolate dehydrogenase increased and that of glutamate formiminotransferase remained constant. In addition, the activities of methylenetetrahydrofolate reductase, methionine synthetase, and methylenetetrahydrofolate dehydrogenase were significantly influenced by postnatal age.
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PMID:Differences in liver folate enzyme patterns in premature and full term infants. 705 Aug 70

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

The subcellular distributions of the enzymes associated with the methylation and cystathionine-synthesizing portion of the sulfur amino acid metabolic pathway have been determined in the occipital lobe of the rhesus monkey. 5-Methyltetrahydrofolate-homocysteine methyltransferase and 5, 10-methylenetetrahydrofolate reductase activities are located mainly in the soluble compartment. Serine hydroxymethyltransferase activity is located primarily in mitochondria. Cystathionine beta-synthase is a soluble enzyme with a significant component occluded within the nerve endings. Glycine, serine, and cystathionine increase per gram of tissue during development. Glycine and serine are approximately 30% occluded within the nerve endings. These data are consistent with a localization of sulfur amino acid metabolism that supports a differential compartmentation of potential neurotransmitter function and methylation function in the primate.
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PMID:Sulfur amino acid metabolism in the developing rhesus monkey brain: subcellular studies of the methylation cycle and cystathionine beta-synthase. 720 68

Periconceptional folate supplementation reduces the risk of neural-tube defects. We studied the frequency of the 677C-->T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene in 55 patients with spina bifida and parents of such patients (70 mothers, 60 fathers). 5% of 207 controls were homozygous for the 677C-->T mutation compared with 16% of mothers, 10% of fathers, and 13% of patients. The mutation was associated with decreased MTHFR activity, low plasma folate, and high plasma homocysteine and red-cell folate concentrations. The 677C-->T mutation should be regarded as a genetic risk factor for spina bifida.
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PMID:Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. 856 8

5-Methyltetrahydrofolate, the major form of folate in plasma, is a carbon donor for the remethylation of homocysteine to methionine. This form of folate is generated from 5,10-methylenetetrahydrofolate through the action of 5,10-methylenetetrahydrofolate reductase (MTHFR), a cytosolic flavoprotein. Patients with an autosomal recessive severe deficiency of MTHFR have homocystinuria and a wide range of neurological and vascular disturbances. We have recently described the isolation of a cDNA for MTHFR and the identification of two mutations in patients with severe MTHFR deficiency. We report here the characterization of seven novel mutations in this gene: six missense mutations and a 5' splice-site defect that activates a cryptic splice site in the coding sequence. We also present a preliminary analysis of the relationship between genotype and phenotype for all nine mutations identified thus far in this gene. A nonsense mutation and two missense mutations (proline to leucine and threonine to methionine) in the homozygous state are associated with extremely low activity (0%-3%) and onset of symptoms within the 1st year of age. Other missense mutations (arginine to cysteine and arginine to glutamine) are associated with higher enzyme activity and later onset of symptoms.
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PMID:Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. 772 58

A 27-year-old woman is described whose disorder meets the DSM-III-R criteria for a diagnosis of schizophrenia and who was found to have a significantly increased serum level of homocysteine. Repeatedly, she improved on frequent cobalamin injections and deteriorated in periods without treatment. The effects of prolonged weekly treatment appeared to diminish as time went on, suggesting that the abnormality was not wholly cobalamin-dependent. It was found that methylenetetrahydrofolate reductase (MR) activity in cultured skin fibroblasts was reduced to a magnitude that is found among people with heterozygous deficiency. A defect in MR activity indicates a deficiency in methyltetrahydrofolate (MTHF), with a consequent reduction of the remethylation of homocysteine to methionine. Thus, reduced methylation may explain the increased levels of homocysteine and the transient effects of cobalamin treatment in the patient. Theoretically, MTHF should be the optimal treatment for her. The case reported highlights the importance of assessing the serum homocysteine level in order to detect methylation deficiency in patients with schizophrenia.
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PMID:Homocysteinemia and schizophrenia as a case of methylation deficiency. 773 11


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