A Glycine N-methyltransferase Knockout Mouse Model for Humans with Deficiency of this Enzyme

Luka, Zigmund; Capdevila, Antonieta; Mato, José M.; Wagner, Conrad

doi:10.1007/s11248-006-0008-1

Cited by 99 publications

(124 citation statements)

References 19 publications

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“…This methylation is thought to provide a means of regulating the level of AdoMet in cells, since the product sarcosine is rapidly reoxidized to glycine in mitochondria. Confirming this role for GNMT, mice completely lacking GNMT due to gene deletion exhibit a ~35-fold increase in AdoMet, with a ~3-fold decrease in AdoHcy [45]. Tissues with high levels of GNMT, such as liver or kidney [46], typically exhibit lower ratios of AdoMet/AdoHcy than do tissues like brain with very low levels of GNMT activity [47].…”

Section: Discussionmentioning

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

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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Section: Discussionmentioning

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

122

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“…8 Consequently, in Gnmt (Ϫ/Ϫ) mice, despite the existence of many other methyltransferases, 9 the liver content of SAMe is increased approximately 25-fold. 10 GNMT is also a major folate binding protein in rat liver, 11 because 5-methyl-tetrahydrofolate (5-MTHF) is a potent inhibitor of GNMT activity. 12,13 This, together with the finding that SAMe is a potent inhibitor of MS activity, an inhibitor of betaine homocysteine methyltransferase (BHMT) activity and expression, and an activator and stabilizer of cystathionine ␤-synthase (CBS, the first step of the transsulfuration pathway) 14 has established the role of GNMT as an important factor in the control of methionine metabolism.…”

Section: Same: Synthesis and Degradationmentioning

confidence: 99%

“…Whereas SAMe depletion predisposes the liver to further injury and possibly malignant degeneration, impaired SAMe metabolism, which occurs in Gnmt (Ϫ/Ϫ) mice 10 and in patients with GNMT mutations, 28 can lead to steatohepatitis, increased hepatocyte apoptosis, fibrosis, and HCC (Mato, Lu, Martínez-Chantar, Luka, Wagner, unpublished observations); and a GNMT polymorphism (1289 C 3 T) has been associated with HCC. 29 These results indicate that liver needs the right amount of SAMe to provide an adequate supply of methyl groups, and that too much or too little SAMe induces liver injury.…”

Section: Role Of Same In Liver Injurymentioning

confidence: 99%

Role of S-adenosyl-L-methionine in liver health and injury

2007

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S-Adenosylmethionine (SAMe) has rapidly moved from being a methyl donor to a key metabolite that regulates hepatocyte growth, death, and differentiation. Biosynthesis of SAMe occurs in all mammalian cells as the first step in methionine catabolism in a reaction catalyzed by methionine adenosyltransferase (MAT). Decreased hepatic SAMe biosynthesis is a consequence of all forms of chronic liver injury. In an animal model of chronic liver SAMe deficiency, the liver is predisposed to further injury and develops spontaneous steatohepatitis and hepatocellular carcinoma. However, impaired SAMe metabolism, which occurs in patients with mutations of glycine N-methyltransferase (GNMT), can also lead to liver injury. This suggest that hepatic SAMe level needs to be maintained within a certain range, and deficiency or excess can both lead to abnormality. SAMe treatment in experimental animal models of liver injury shows hepatoprotective properties. Meta-analyses also show it is effective in patients with cholestatic liver diseases. Recent data show that exogenous SAMe can regulate hepatocyte growth and death, independent of its role as a methyl donor. This raises the question of its mechanism of action when used pharmacologically. Indeed, many of its actions can be recapitulated by methylthioadenosine (MTA), a by-product of SAMe that is not a methyl donor. A better understanding of why liver injury occurs when SAMe homeostasis is perturbed and mechanisms of action of pharmacologic doses of SAMe are essential in defining which patients will benefit from its use. (HEPATOLOGY 2007;45: 1306-1312.)

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“…Yi-Cheng Wang, 1 Yi-Ming Chen, 2* Yan-Jun Lin, 1 Shih-Ping Liu, 2 and En-Pei Isabel Chiang of GNMT had significant impacts on methyl donor S-adenosylmethionine supplies as well as the S-adenosylmethionine to S-adenosylhomocysteine balance (8)(9)(10). Deletion of GNMT increased the susceptibility of liver cancer in mice (10).…”

Section: Gnmt Expression Increases Hepatic Folate Contents and Folatementioning

confidence: 99%

“…GNMT is also a major hepatic folate-binding protein (2,3) that binds to, and, subsequently, may be inhibited by 5-methyl-THF (2). The expression and function of GNMT have been investigated in human diseases (4-7) and mouse models (8)(9)(10). Downregulation of GNMT has also been reported in human hepatocellular carcinoma.…”

Section: Introductionmentioning

confidence: 99%

GNMT Expression Increases Hepatic Folate Contents and Folate-Dependent Methionine Synthase-Mediated Homocysteine Remethylation

Wang

Lin

Liu³

et al. 2011

Mol Med

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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.

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A Glycine N-methyltransferase Knockout Mouse Model for Humans with Deficiency of this Enzyme

Cited by 99 publications

References 19 publications

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

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

Role of S-adenosyl-L-methionine in liver health and injury

GNMT Expression Increases Hepatic Folate Contents and Folate-Dependent Methionine Synthase-Mediated Homocysteine Remethylation

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