Mammalian methylenetetrahydrofolate reductase Partial purification, properties, and inhibition by S-adenosylmethionine

Kutzbach, Carl; Stokstad, E. L. R.

doi:10.1016/0005-2744(71)90247-6

Cited by 331 publications

(185 citation statements)

References 29 publications

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“…24) Furthermore, it is known that SAM, which increases in response to the amount of methionine ingested, inhibits 5,10-methylenetetrahydrofolate reductase, a key enzyme in the formation of 5-methyltetrahydrofolate. 26) These facts suggest that the 5-methyltetrahydrofolate-dependent remethylation of homocysteine is depressed under the condition of methionine loading. Since glycine and serine both suppressed the methionine-induced increase in hepatic SAM concentration, the possibility that these amino acids may stimulate the formation of 5-methyltetrahydrofolate and thereby enhance the removal of homocysteine cannot be completely excluded.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Methionine-Induced Hyperhomocysteinemia by Glycine and Serine in Rats

Fukada

Shimada

Morita

et al. 2006

Bioscience, Biotechnology, and Biochemistry

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The hyperhomocysteinemia induced by a dietary addition of 1% methionine was significantly suppressed by the concurrent addition of 1% glycine or 1.4% serine to the same degree. The methionine-induced increase in the hepatic concentration of methionine metabolites was significantly suppressed by glycine and serine, but the hepatic cystathionine -synthase activity was not enhanced by these amino acids. When the methioninesupplemented diet was changed to the methionine plus glycine or serine diet, the plasma homocysteine concentration rapidly decreased during and after the first day. The hyperhomocysteinemia induced by an intraperitoneal injection with methionine was also suppressed by concurrent injection with glycine or serine, although the effect of serine was significantly greater than that of glycine. These results indicate that glycine and serine were effective for suppressing methionine-induced hyperhomocysteinemia: serine and its precursor glycine are considered to have elicited their effects mainly by stimulating cystathionine synthesis by supplying serine, another substrate for cystathionine synthesis.

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Section: Discussionmentioning

confidence: 99%

Suppression of Methionine-Induced Hyperhomocysteinemia by Glycine and Serine in Rats

Fukada

Shimada

Morita

et al. 2006

Bioscience, Biotechnology, and Biochemistry

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“…5,lO-Methylenetetrahydrofolate reductase was assayed spectrophotometrically according to Kutzbach et al [15], using an expanded scale (0-0.2). One unit of enzyme activity is the amount of enzyme catalysing the formation of 1 nmol product per min.…”

Section: Enzyme Assaysmentioning

confidence: 99%

Mitochondrial and Cytoplasmic Distribution in Saccharomyces cerevisiae of Enzymes Involved in Folate‐Coenzyme‐Mediated One‐Carbon‐Group Transfer

Zelikson

Luzzati

1977

European Journal of Biochemistry

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The study of the subcellular distribution of the enzymes involved in folate-coenzyme-mediated transfer of one-carbon groups in Saccharomyces cerevisiae suggests the existence of two parallel enzyme systems, one mitochondrial and the other cytoplasmic. All the enzymes assayed in the present study, serine transhydroxymethylase, dihydrofolate reductase, 5,lO-methylenetetrahydrofolate dehydrogenase, 10-formyltetrahydrofolate synthetase, 5,lO-methylenetetrahydrofolate reductase and thymidylate synthetase were found to be in both cytoplasm and mitochondria. Two of the mitochondrial enzymes, serine transhydroxymethylase and dihydrofolate reductase, were found to be different by several criteria from their cytoplasmic counterparts.By the use of three nuclear gene mutations ade3, tmp3 and serl, and different combinations of these three mutations, the physiological role of the cytoplasmic enzymes for the biosynthesis of adenine, histidine, methionine, thymidylate and serine was studied. The response of auxotrophes to an external source of tetrahydrofolate, i. e. 5-formyl tetrahydrofolic acid, was also examined. The mitochondrial set of enzymes might be responsible for the de novo formation of tetrahydrofolate, since the loss of the three mitochondrial enzyme activities, serine transhydroxymethylase, thymidylate synthetase and dihydrofolate reductase, due to the mutation tmp3, leads to a generalized requirement for thymidylate, methionine, adenine and histidine. The ade3 mutation in which the cytoplasmic activities of the 10-formyltetrahydrofolate synthetase, 5,lO-methenyltetrahydrofolate cyclohydrolase and 5,lO-methylenetetrahydrofolate dehydrogenase are lost, confers only adenine and histidine auxotrophy, showing that the ade3 proteins are synthesized in, and only function in, the cytoplasm. The mitochondrial counterparts of these enzymes may function solely in the formation of the 10-formyl tetrahydrofolate needed for the transformylation of Met-tRNA involved in mitochondrial protein synthesis.A study of a nuclear mutation in Saccharomyces cerevisiae, tmp3, leading concomittantly to multiple nutritional requirements for thymidylate, methionine, adenine and histidine and to the petite phenotype, was found to have a decreased activity of serine transhydroxymethylase, but a wild-type level of two other tetrahydrofolate-linked enzymes, 10-formylte- trahydrofolate-linked enzymes, 10-formyltetrahydrofolate synthetase and 5,1O-methylenetetrahydrofolate dehydrogenase [l]. Further study showed that wildtype strains of yeast have two forms of serine transhydroxymethylase, one cytoplasmic and the other mitochondrial, separable by TEAE-cellulose chromatography. The mutant tmp3 has lost the mitochondrial form [2].Serine transhydroxymethylase may be the major physiological source of 5,lO-methylene tetrahydrofolate needed for the formation of methionine, thymidylate and adenine. Loss of the mitochondrial enzyme, in tmp3, which leads to that multiple requirement, implies that either the mitochondrial serine transhydroxymethylase is the...

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“…During primary turnover, methionine synthase acquires methyl groups from methyltetrahydrofolate, which is generated by the reduction of methylenetetrahydrofolate (CH 2 =THF) catalyzed by methylenetetrahydrofolate reductase. The methylenetetrahydrofolate reductase reaction is irreversible under physiological conditions and is inhibited allosterically by the presence of AdoMet [3,4]. In this way, methyl groups from the folate pathway are committed as needed to the production of methionine for AdoMet biosynthesis and other processes requiring methionine.…”

Section: Introductionmentioning

confidence: 99%

Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase

Elmore

Leclerc

et al. 2007

Molecular Genetics and Metabolism

100

122

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Hyperhomocyst(e)inemia is a metabolic derangement that is linked to the distribution of folate pools, which provide one-carbon units for biosynthesis of purines and thymidylate and for remethylation of homocysteine to form methionine. In humans, methionine synthase deficiency results in the accumulation of methyltetrahydrofolate at the expense of folate derivatives required for purine and thymidylate biosynthesis. Complete ablation of methionine synthase activity in mice results in embryonic lethality. Other mouse models for hyperhomocyst(e)inemia have normal or reduced levels of methyltetrahydrofolate and are not embryonic lethal, although they have decreased ratios of AdoMet/AdoHcy and impaired methylation. We have constructed a mouse model with a gene trap insertion in the Mtrr gene specifying methionine synthase reductase, an enzyme essential for the activity of methionine synthase. This model is a hypomorph, with reduced methionine synthase reductase activity, thus avoiding the lethality associated with the absence of methionine synthase activity. Mtrr gt/gt mice have increased plasma homocyst(e)ine, decreased plasma methionine, and increased tissue methyltetrahydrofolate. Unexpectedly, Mtrr gt/gt mice do not show decreases in the AdoMet/AdoHcy ratio in most tissues. The different metabolite profiles in the various genetic mouse models for hyperhomocysteinemia may be useful in understanding biological effects of elevated homocyst(e)ine.

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Mammalian methylenetetrahydrofolate reductase Partial purification, properties, and inhibition by S-adenosylmethionine

Cited by 331 publications

References 29 publications

Suppression of Methionine-Induced Hyperhomocysteinemia by Glycine and Serine in Rats

Suppression of Methionine-Induced Hyperhomocysteinemia by Glycine and Serine in Rats

Mitochondrial and Cytoplasmic Distribution in Saccharomyces cerevisiae of Enzymes Involved in Folate‐Coenzyme‐Mediated One‐Carbon‐Group Transfer

Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase

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