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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)

Most mammalian cells receive exogenous folate from the bloodstream in the form of 5-methyltetrahydropteroylmonoglutamate (CH3-H4PteGlu1). Because this folate derivative is a very poor substrate for folylpolyglutamate synthetase, the enzyme that adds glutamyl residues to intracellular folates, CH3-H4PteGlu1 must first be converted to tetrahydropteroylmonoglutamate (H4PteGlu1), 10-formyltetrahydropteroylmonoglutamate (CHO-H4PteGlu1), or dihydrofolate (H2folate), which are excellent substrates for folylpolyglutamate synthetase. Polyglutamylation is required both for retention of intracellular folates and for efficacy of folates as substrates for most folate-dependent enzymes. Two enzymes are known that will react with CH3-H4PteGlu1 in vitro, methylenetetrahydrofolate reductase and methyltetrahydrofolate-homocysteine methyltransferase (cobalamin-dependent methionine synthase). These studies were performed to assess the possibility that methylenetetrahydrofolate reductase might catalyze the conversion of CH3-H4PteGlu1 to CH2-H4PteGlu1. CH2-H4PteGlu1 is readily converted to CHO-H4PteGlu1 by the action of methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase, and these enzyme activities show very little preference for folypolyglutamate substrates as compared with folylmonoglutamates. We conclude from in vitro studies of the enzyme that methylenetetrahydrofolate reductase cannot convert CH3-H4PteGlu1 to CH2-H4PteGlu1 under physiological conditions and that uptake and retention of folate will be dependent on methionine synthase activity.
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PMID:Examination of the role of methylenetetrahydrofolate reductase in incorporation of methyltetrahydrofolate into cellular metabolism. 333 80

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

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