Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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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)

The concentration and polyglutamate status of 5-methyltetrahydrofolate in mouse liver tissue extracts has been determined by enzymatic conversion to methylenetetrahydrofolate and subsequent entrapment of this cofactor form into a ternary complex with Lactobacillus casei thymidylate synthase and tritiated 5-fluorodeoxyuridylate. 5-Methyltetrahydrofolate was oxidized to methylenetetrahydrofolate using the reverse reaction of methylenetetrahydrofolate reductase with menadione as the ultimate electron acceptor. Reference 5-methyltetrahydrofolate could be quantitatively recovered from tissue extracts by this method. The polyglutamate status of enzymatically converted and complexed tissue 5-methyltetrahydrofolate was determined electrophoretically. Unlabeled 5-fluorodeoxyuridylate was used to remove endogenous methylenetetrahydrofolate prior to enzymatic oxidation of 5-methyltetrahydrofolate and subsequent electrophoretic analysis. In this manner, the 5-methyltetrahydrofolate polyglutamate pool alone could be labeled and visualized. There were no observable differences in the polyglutamate distribution of endogenous methylenetetrahydrofolate versus 5-methyltetrahydrofolate polyglutamates in extracts of normal mouse liver tissue.
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PMID:Determination of mouse liver 5-methyltetrahydrofolate concentration and polyglutamate forms. 399 82

1. The concentrations of folate derivatives in aerobic cultures of Saccharomyces cerevisiae (A.T.C.C. 9763) were determined by microbiological assay employing Lactobacillus casei (A.T.C.C. 7469) and Pediococcus cerevisiae (A.T.C.C. 8081). Cells cultured in media lacking l-methionine contained higher concentrations of folate derivatives than cells grown in the same media supplemented with 2.5mumol of l-methionine/ml. The concentrations of highly conjugated derivatives were also decreased by supplementing the growth medium with l-methionine. 2. DEAE-cellulose column chromatography of extracts prepared from cells grown under these conditions revealed that the concentrations of methylated tetrahydrofolates were drastically decreased by the methionine supplement. Smaller decreases were also observed in the concentrations of formylated and unsubstituted derivatives. 3. The concentrations of four enzymes of C(1) metabolism were compared after 6h of growth in the presence and in the absence of l-methionine (2.5mumol/ml). The specific activities of formyltetrahydrofolate synthetase, methylenetetrahydrofolate reductase and serine hydroxymethyltransferase were not altered by this treatment but that of 5-methyltetrahydrofolate-homocysteine methyltransferase was decreased by approx. 65% when l-methionine was supplied. The activities of 5-methyltetrahydrofolate-homocysteine methyltransferase, serine hydroxymethyltransferase and formyltetrahydrofolate synthetase were not appreciably altered by l-methionine in vitro. In contrast this amino acid was found to inhibit the activity of methylenetetrahydrofolate reductase. 4. Feeding experiments employing sodium [(14)C]formate indicated that cells grown in the presence of exogenous methionine, although having less ability to convert formate into methionine, readily incorporated (14)C into serine and the adenosyl moiety of S-adenosylmethionine. 5. It is suggested that exogenous l-methionine controls C(1) metabolism in Saccharomyces principally by regulation of methyl-group biogenesis within the folate pool.
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PMID:Regulation of C metabolism by L-methionine in Saccharomyces cerevisiae. 419 57

Methyltetrahydrofolate synchronizes the activities of the two branches of the pathway of methionine biosynthesis in Neurospora crassa by serving as an essential activator of cystathionine gamma-synthase and antagonizing the feedback inhibition of this enzyme by S-adenosylmethionine. Activation is specific for the methylated form of folate and increases with increasing glutamate content. The inability of extracts of me-1 and me-6 mutants to form cystathionine that has been previously reported is due to the absence of N(5)-methyltetrahydrofolate from these preparations. Extracts of me-1 mutants lack methyltetrahydrofolate because the organisms are deficient in methylenetetrahydrofolate reductase, and those of me-6 because their methyltetrahydrofolate is quantitatively removed by the procedure employed in the preparation of extracts. The folate of the me-6 organisms differs from that of wild type strains in consisting largely of the monoglutamate rather than higher conjugates.
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PMID:Synchronization of converging metabolic pathways: activation of the Cystathionine gamma-synthase of Neurospora crassa by methyltetrahydrofolate. 527 76

1. Following the genetic studies by Smith (1961) and Smith & Childs (1963) with methionine auxotrophs of Salmonella typhimurium, methionine formation from homocysteine has been investigated with cell-free extracts of this organism. 2. As found with Escherichia coli (Woods, Foster & Guest, 1964), methyl groups are formed by an N(5)N(10)-methylenetetrahydrofolate reductase. They are then transferred to homocysteine by either a simple N(5)-methyltetrahydropteroyl-triglutamate-homocysteine methyltransferase or alternatively a cobalamin-dependent N(5)-methyltetrahydrofolate-homocysteine methyltransferase. 3. S. typhimurium differs from E. coli in being able to synthesize significant amounts of cobalamin.
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PMID:Methionine synthesis by extracts of Salmonella typhimurium. 532 68

A greater number of inherited metabolic disorders can now be treated with special diets or cofactors. Recent progress is illustrated by the example of various hyperphenylalaninaemias (HPHE), of maple syrup urine disease (MSUD) and of various homocystinurias (HCY). Of special importance for the future is a severe embryopathy in infants of mothers with HPHE and its possible prevention by reintroducing a phenylalanine - restricted diet for the mother before conception. Of considerable scientific interest and therapeutic impact is also the treatment of patients with HPHE due to tetrahydrobiopterin deficiency. This consists in substituting the patients' metabolism with this cofactor of phenylalanine hydroxylase as well as with neurotransmitters. Cofactor deficiencies have also been described in MSUD and HCY, and substitution with high doses of thiamine and pyridoxin has been successful. The management of the acute metabolic derangement of neonatal MSUD is a great therapeutic challenge even to experienced metabolic centres. Rational therapy for homocystinurias due to remethylation defects is still being explored. In siblings with methylenetetrahydrofolate reductase deficiency we used leucovorin for the first time and with success.
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PMID:[Diet therapy and coenzyme therapy in hereditary metabolic diseases]. 613 9

The folacin-depleting effect of phenytoin has been known clinically for many years, but a systematic investigation of this effect in animals has never been undertaken. In this study we found that chronic oral phenytoin treatment (100 mg/kg every 12 hours for 8 weeks) in rats significantly affected concentrations of folates in both liver and brain. Concentration of liver folates dropped to one-third the normal level even though concentration of plasma folates was not affected. Concentration of brain folates increased over the first 2 weeks of treatment and then declined to a level approximately three-fourths the normal concentration. The apparent activity of 5,10-methylenetetrahydrofolate reductase (MTR) increased as a function of the length of treatment in both brain and liver, but when phenytoin was added to the MTR assay in vitro, the activity was inhibited. No significant effects of phenytoin on the activities of serine hydroxymethyltransferase (SHMT), 5-methyltetrahydrofolate:homocysteine methyltransferase (MHMT) or methionine adenosyltransferase (MAT) were observed either in vivo or in vitro. These data are consistent with the hypothesis that phenytoin interacts with the metabolism of folates at the enzymatic level.
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PMID:The effect of chronic phenytoin treatment on tissue folate concentrations and on the activities of the methyl synthetic enzymes in the rat. 635 8

Scanning transmission electron microscopy of individual unfixed molecules of methylenetetrahydrofolate reductase has been used to determine the molecular mass distribution of the protein. Methylenetetrahydrofolate reductase, which has a subunit molecular mass of 77 kilodaltons, was found to exist predominantly as a dimer with an apparent molecular mass of 136 +/- 29 kilodaltons. The mass distribution of the enzyme molecules was unchanged in the presence of the allosteric inhibitor S-adenosylmethionine. Examination of negatively stained protein molecules suggested that each subunit of the dimer consists of two globular domains of approximately equal size. Limited proteolysis of the enzyme by trypsin gave results which were entirely consistent with the presence of two domains per subunit. In the presence of 1% trypsin, the enzyme was cleaved into two fragments. The masses of these fragments were 39 and 36 kilodaltons as assessed by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Tryptic cleavage did not lead to loss of NADPH-menadione or NADPH-methylenetetrahydrofolate oxidoreductase activity, and the flavin prosthetic group remained bound to the protein. However, the cleaved protein was completely desensitized with respect to inhibition by S-adenosylmethionine. These results suggest that each subunit of methylenetetrahydrofolate reductase contains two domains and that allosteric inhibition requires specific interactions between these domains. The region between these two domains appears to be very sensitive to proteolysis, while the domains themselves are relatively resistant to further degradation.
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PMID:Methylenetetrahydrofolate reductase. Evidence for spatially distinct subunit domains obtained by scanning transmission electron microscopy and limited proteolysis. 638 10

Chronic oral phenobarbital treatment (50 mg/kg every 12 hr for 8 weeks), which was nontoxic and continuously protective against seizures in rats, significantly decreased folate concentration in liver (29%) but not in brain or plasma. The apparent activity of 5,10-methylenetetrahydrofolate reductase (MTR) in liver decreased with initiation of treatment but then increased with a significant correlation to the length of treatment. Phenobarbital also stimulated the activity of this enzyme slightly in vitro. Methionine adenosyltransferase (MAT) activity was inhibited by high concentrations of phenobarbital in vitro but was not affected in vivo. No significant effects of phenobarbital on the activities of serine hydroxymethyltransferase (SHMT) or 5-methyltetrahydrofolate:homocysteine methyltransferase (MHMT) were observed either in vivo or in vitro.
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PMID:Effect of chronic phenobarbital treatment on folates and one-carbon enzymes in the rat. 638 80

Previous work from this laboratory has established that the NADPH-menadione oxidoreductase reaction catalyzed by methylenetetrahydrofolate reductase from pig liver proceeds by Ping Pong Bi Bi kinetics and that the reductive half-reaction is rate limiting in steady-state turnover. We have now shown that methylenetetrahydrofolate reductase stereo-specifically removes the pro-S hydrogen from the 4-position of NADPH. During the oxidation of [4(S)-3H]NADPH, we observed a kinetic isotope on V/KNADPH of 10.8 +/- 0.4. When comparing the rates of oxidation of [4(S)-2H]NADPH and [4(S)-1H]NADPH, we measure kinetic isotope effects on V of 4.78 +/- 0.15 and on V/KNADPH of 4.54 +/- 0.59. When oxidation of [4(R)-2H]NADPH and [4(R)-1H]NADPH is compared, the secondary kinetic isotope effect on V is 1.04 +/- 0.01. When the NADPH-menadione oxidoreductase reaction is catalyzed in tritiated water, no incorporation of solvent tritium into residual NADPH is observed. We conclude from these observations that the oxidation of NADPH is largely or entirely rate limiting in the reductive half-reaction and, hence, in NADPH-menadione oxidoreductase turnover at saturating menadione concentration. In the presence of saturating NADPH, the flavin reduction proceeds with a rate constant of 160 S-1, which is at least 29-fold slower than estimates of the lower limit for the diffusion-limited rate constant characterizing NADPH binding to the enzyme under physiological conditions. Albery & Knowles have defined criteria for perfection in enzyme catalysis [Albery, W. J., & Knowles, J.R. (1976) Biochemistry 15, 5631-5640].(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Kinetic isotope effects on the oxidation of reduced nicotinamide adenine dinucleotide phosphate by the flavoprotein methylenetetrahydrofolate reductase. 639 40

The activity of 4 enzymes involved in the formation and interconversion of folate coenzymes has been examined in liver and kidney of healthy and Ehrlich ascites carcinoma-bearing mice. In the liver, a 50% increase of methylenetetrahydrofolate reductase activity was shown soon after tumour cell inoculation, while the activity of formyltetrahydrofolate synthetase and methylenetetrahydrofolate dehydrogenase decrease by 20% at an advanced stage of tumour development. In kidneys of the host mouse the only change observed was a decrease of dihydrofolate reductase activity. The levels of activity of all assayed enzymes found in host organs were similar to that in Ehrlich carcinoma cells.
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PMID:Folate enzymes in Ehrlich ascites carcinoma-bearing mice. 639 50


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