Please use this identifier to cite or link to this item:
標題: GNMT Expression Increases Hepatic Folate Contents and Folate-Dependent Methionine Synthase-Mediated Homocysteine Remethylation
作者: Wang, Yi-Cheng
Chen, Yi-Ming
Lin, Yan-Jun
Liu, Shih-Ping
Chiang, En-Pei Isabel
關鍵字: glycine-n-methyltransferase;one-carbon metabolism;human;hepatocellular-carcinoma;tumor susceptibility gene;binding-protein;rat-liver;methylenetetrahydrofolate reductase;s-adenosylmethionine;dna methylation;mathematical-model
Project: Molecular Medicine, Volume 17, Issue 5-6, Page(s) 486-494.
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. (C) 2011 The Feinstein Institute for Medical Research, Online address: doi: 10.2119/molmed.2010.00243
ISSN: 1076-1551
DOI: 10.2119/molmed.2010.00243
Appears in Collections:食品暨應用生物科技學系

Show full item record

Google ScholarTM




Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.