Feedback inhibition of methylene-tetrahydrofolate reductase in rat liver by S-adenosylmethionine

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

doi:10.1016/0005-2744(67)90140-4

Cited by 190 publications

(69 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We demonstrated that transformed human lymphoblasts with reduced methylene tetrahydrofolate reductase (MTHFR) have advantages in de novo purine synthesis when folate is adequate, but they are more susceptible to S-adenosylmethionine depletion when folate is restricted (21). MTHFR, the enzyme that catalyzes the irreversible conversion of 5,10-methylene-tetrahydrofolate to 5-methyl-THF, is inhibited by S-adenosylmethionine (22)(23). In mammals, the only known reaction that requires 5-methyl-THF is the synthesis of methionine from homocysteine (16).…”

Section: Gnmt Expression Increases Hepatic Folate Contents and Folatementioning

confidence: 99%

Involvement of Leptin Receptor Long Isoform (LepRb)-STAT3 Signaling Pathway in Brain Fat Mass- and Obesity-Associated (FTO) Downregulation during Energy Restriction

Wang

Yang

et al. 2011

Mol Med

View full text Add to dashboard Cite

Glycine N-methyltransferase (GNMT) is a major hepatic enzyme that converts S-adenosylmethionine to S-adenosylhomocysteine while generating sarcosine from glycine, hence it can regulate mediating methyl group availability in mammalian cells. GNMT is also a major hepatic folate binding protein that binds to, and, subsequently, may be inhibited by 5-methyltetrafolate. GNMT is commonly diminished in human hepatoma; yet its role in cellular folate metabolism, in tumorigenesis and antifolate therapies, is not understood completely. In the present study, we investigated the impacts of GNMT expression on cell growth, folate status, methylfolate-dependent reactions and antifolate cytotoxicity. GNMT-diminished hepatoma cell lines transfected with GNMT were cultured under folate abundance or restriction. Folate-dependent homocysteine remethylation fluxes were investigated using stable isotopic tracers and gas chromatography/mass spectrometry. Folate status was compared between wild-type (WT), GNMT transgenic (GNMT tg ) and GNMT knockout (GNMT ko ) mice. In the cell model, GNMT expression increased folate concentration, induced folate-dependent homocysteine remethylation, and reduced antifolate methotrexate cytotoxicity. In the mouse models, GNMT tg had increased hepatic folate significantly, whereas GNMT ko had reduced folate. Liver folate levels correlated well with GNMT expressions (r = 0.53, P = 0.002); and methionine synthase expression was reduced significantly in GNMT ko , demonstrating impaired methylfolate-dependent metabolism by GNMT deletion. In conclusion, we demonstrated novel findings that restoring GNMT assists methylfolate-dependent reactions and ameliorates the consequences of folate depletion. GNMT expression in vivo improves folate retention and bioavailability in the liver. Studies on how GNMT expression impacts the distribution of different folate cofactors and the regulation of specific folate dependent reactions are underway.

show abstract

Section: Gnmt Expression Increases Hepatic Folate Contents and Folatementioning

confidence: 99%

Involvement of Leptin Receptor Long Isoform (LepRb)-STAT3 Signaling Pathway in Brain Fat Mass- and Obesity-Associated (FTO) Downregulation during Energy Restriction

Wang

Yang

et al. 2011

Mol Med

View full text Add to dashboard Cite

show abstract

“…The assay procedure of Donaldson and Keresztesy (5) for measuring methylene-H,PteGlu reductase activity in the socalled reverse direction using menadione as the electron acceptor, shown in reaction 3 , was performed according to a modification of the method of Kutzbach and Stokstad (14,15). menadione-HZ menadione…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, the regulation of methylene-H,PteGlu, which catalyzes 5-methyl-H,PtcGlu synthesis, has been less well characterized in cultured mammalian cells. The reductase of rat and hog liver has bcen extensively purificd and studied (14). Methylcnc-H,PteGlu reductase activity is present in extracts of cultured human skin fibrobasts (7,18,21).…”

Section: Speculationmentioning

confidence: 99%

Methylenetetrahy drofolate Reductase in Cultured Human Cells. I. Growth and Metabolic Studies

Rosenblatt

Erbe

1977

Pediatr Res

View full text Add to dashboard Cite

Summarycystcinc cobalamin methyltransfcrase, which catalyzes the utilThis investigation examined factors that affect methylenetetrahydrofolate-(rnethylene-~,~te~lu) reductase activity in cultured human cells. Activitv was demonstrable in extracts of cultured normal human skin"fibroblasts, amniotic fluid cells, and lymphoblasts. The velocity of the reaction was maximal a t pH 6.3 in extracts of all three cell types. Subcellular localization studies indicated that 83-94% of the reductase activity was extranuclear in the three cell types. The reductase activity was not substantially altered by growth of lymphoblasts whether in Eagle's minimum essential medium (MEM) supplemented with homocysteine alone or with additional hydroxocobalamin and folic acid, o r in media containing a 5-fold greater concentration of methionine. In normal fibroblasts the methylene-H,PteGlu reductase activitv varied little when the confluent cells were exposed to media deficient in o r supplemented with varying amounts and combinations of methionine, homocysteine, folic acid, and cobalamin. Under our conditions the addition of purified S-adenosylmethionine to give a final concentration of 48 mM in the assay reaction mixture reduced the reductase activity to 38% of control in the fibroblast extract and to 13% of control in the extract of rat liver. This sensitivity to inhibition by Sadenosylmethionine and the lack of response to varied levels of methionine, homocysteine, folic acid, and cobalamin are further evidence that the reductase activities in mammalian liver and fibroblasts are similar.

show abstract

“…MTHFR catalyzes the irreversible conversion of 5,10-methylene-THF to 5-methyl-THF, and it is inhibited by adoMet (21). This enzyme plays an important role in cellular folate coenzyme cycling and the partitioning of 1C units.…”

Section: Genetic Variations Of Mthfr Modulate Cancer Riskmentioning

confidence: 99%

Regulation of Folate-Mediated One-Carbon Metabolism by Glycine <i>N</i>-Methyltransferase (GNMT) and Methylenetetrahydrofolate Reductase (MTHFR)

Wang

Lin

et al. 2015

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

View full text Add to dashboard Cite

Feedback inhibition of methylene-tetrahydrofolate reductase in rat liver by S-adenosylmethionine

Cited by 190 publications

References 8 publications

Involvement of Leptin Receptor Long Isoform (LepRb)-STAT3 Signaling Pathway in Brain Fat Mass- and Obesity-Associated (FTO) Downregulation during Energy Restriction

Involvement of Leptin Receptor Long Isoform (LepRb)-STAT3 Signaling Pathway in Brain Fat Mass- and Obesity-Associated (FTO) Downregulation during Energy Restriction

Methylenetetrahy drofolate Reductase in Cultured Human Cells. I. Growth and Metabolic Studies

Regulation of Folate-Mediated One-Carbon Metabolism by Glycine <i>N</i>-Methyltransferase (GNMT) and Methylenetetrahydrofolate Reductase (MTHFR)

Contact Info

Product

Resources

About