Glycine N-Methyltransferase

Publication Title: 
Biochimica Et Biophysica Acta

This review describes our current understanding of the "traffic lights" that regulate sulfur flow through the methionine bionetwork in liver, which supplies two major homeostatic systems governing cellular methylation and antioxidant potential. Theoretical concepts derived from mathematical modeling of this metabolic nexus provide insights into the properties of this system, some of which seem to be paradoxical at first glance. Cellular needs supported by this network are met by use of parallel metabolic tracks that are differentially controlled by intermediates in the pathway.

Author(s): 
Martinov, M. V.
Vitvitsky, V. M.
Banerjee, R.
Ataullakhanov, F. I.
Publication Title: 
Hepatology (Baltimore, Md.)

Glycine N-methyltransferase (GNMT) is the main enzyme responsible for catabolism of excess hepatic S-adenosylmethionine (SAMe). GNMT is absent in hepatocellular carcinoma (HCC), messenger RNA (mRNA) levels are significantly lower in livers of patients at risk of developing HCC, and GNMT has been proposed to be a tumor-susceptibility gene for liver cancer. The identification of several children with liver disease as having mutations of the GNMT gene further suggests that this enzyme plays an important role in liver function.

Author(s): 
Martínez-Chantar, M. Luz
Vázquez-Chantada, Mercedes
Ariz, Usue
Martínez, Núria
Varela, Marta
Luka, Zigmund
Capdevila, Antonieta
Rodríguez, Juan
Aransay, Ana M.
Matthiesen, Rune
Yang, Heping
Calvisi, Diego F.
Esteller, Manel
Fraga, Mario
Lu, Shelly C.
Wagner, Conrad
Mato, José M.
Publication Title: 
Hepatology (Baltimore, Md.)

Hepatic S-adenosylmethionine (SAMe) is maintained constant by the action of methionine adenosyltransferase I/III (MATI/III), which converts methionine into SAMe and glycine N-methyltransferase (GNMT), which eliminates excess SAMe to avoid aberrant methylation reactions. During liver regeneration after partial hepatectomy (PH) MATI/III activity is inhibited leading to a decrease in SAMe. This injury-related reduction in SAMe promotes hepatocyte proliferation because SAMe inhibits hepatocyte DNA synthesis.

Author(s): 
Varela-Rey, Marta
Fernández-Ramos, David
Martínez-López, Nuria
Embade, Nieves
Gomez-Santos, Laura
Beraza, Naiara
Vázquez-Chantada, Mercedes
Rodríguez, Juan
Luka, Zigmund
Wagner, Conrad
Lu, Shelly C.
Martínez-Chantar, M. Luz
Mato, José M.
Publication Title: 
Experimental and Molecular Pathology

Regeneration of the liver is inhibited as a result of a sustained increase in S-adenosylmethionine levels in glycine N-methyltransferase (GNMT)-/- mice. This sets the stage for normally dormant stem cells/progenitor cells to replicate and differentiate to replenish the liver parenchyma with liver cells. With time the stem cells/progenitor cells may aggregate and ultimately form liver tumors. This transformation of stem cells persists within the tumors that form in order to maintain the growth of the tumors that have formed.

Author(s): 
Martínez-Chantar, M. L.
Lu, S. C.
Mato, J. M.
Luka, Z.
Wagner, C.
French, B. A.
French, S. W.
Publication Title: 
Gastroenterology

BACKGROUND & AIMS: Hepatic de-differentiation, liver development, and malignant transformation are processes in which the levels of hepatic S-adenosylmethionine are tightly regulated by 2 genes: methionine adenosyltransferase 1A (MAT1A) and methionine adenosyltransferase 2A (MAT2A). MAT1A is expressed in the adult liver, whereas MAT2A expression primarily is extrahepatic and is associated strongly with liver proliferation. The mechanisms that regulate these expression patterns are not completely understood.

Author(s): 
Vázquez-Chantada, Mercedes
Fernández-Ramos, David
Embade, Nieves
Martínez-López, Nuria
Varela-Rey, Marta
Woodhoo, Ashwin
Luka, Zigmund
Wagner, Conrad
Anglim, Paul P.
Finnell, Richard H.
Caballeria, Juan
Laird-Offringa, Ite A.
Gorospe, Myriam
Lu, Shelly C.
Mato, José M.
Martínez-Chantar, M. Luz
Publication Title: 
Hepatology (Baltimore, Md.)

Deletion of glycine N-methyltransferase (GNMT), the main gene involved in liver S-adenosylmethionine (SAM) catabolism, leads to the hepatic accumulation of this molecule and the development of fatty liver and fibrosis in mice. To demonstrate that the excess of hepatic SAM is the main agent contributing to liver disease in GNMT knockout (KO) mice, we treated 1.5-month-old GNMT-KO mice for 6 weeks with nicotinamide (NAM), a substrate of the enzyme NAM N-methyltransferase.

Author(s): 
Varela-Rey, Marta
Martínez-López, Nuria
Fernández-Ramos, David
Embade, Nieves
Calvisi, Diego F.
Woodhoo, Aswhin
Rodríguez, Juan
Fraga, Mario F.
Julve, Josep
Rodríguez-Millán, Elisabeth
Frades, Itziar
Torres, Luís
Luka, Zigmund
Wagner, Conrad
Esteller, Manel
Lu, Shelly C.
Martínez-Chantar, M. Luz
Mato, José M.
Publication Title: 
Journal of Proteome Research

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in most western countries. Current NAFLD diagnosis methods (e.g., liver biopsy analysis or imaging techniques) are poorly suited as tests for such a prevalent condition, from both a clinical and financial point of view. The present work aims to demonstrate the potential utility of serum metabolic profiling in defining phenotypic biomarkers that could be useful in NAFLD management.

Author(s): 
Barr, Jonathan
Vázquez-Chantada, Mercedes
Alonso, Cristina
Perez-Cormenzana, Miriam
Mayo, Rebeca
Galán, Asier
Caballeria, Juan
Martín-Duce, Antonio
Tran, Albert
Wagner, Conrad
Luka, Zigmund
Lu, Shelly C.
Castro, Azucena
Le Marchand-Brustel, Yannick
Martínez-Chantar, M. Luz
Veyrie, Nicolas
Clément, Karine
Tordjman, Joan
Gual, Philippe
Mato, José M.
Publication Title: 
Hepatology (Baltimore, Md.)

Glycine N-methyltransferase (GNMT) catabolizes S-adenosylmethionine (SAMe), the main methyl donor of the body. Patients with cirrhosis show attenuated GNMT expression, which is absent in hepatocellular carcinoma (HCC) samples. GNMT(-/-) mice develop spontaneous steatosis that progresses to steatohepatitis, cirrhosis, and HCC. The liver is highly enriched with innate immune cells and plays a key role in the body's host defense and in the regulation of inflammation. Chronic inflammation is the major hallmark of nonalcoholic steatohepatitis (NASH) progression.

Author(s): 
Gomez-Santos, Laura
Luka, Zigmund
Wagner, Conrad
Fernandez-Alvarez, Sara
Lu, Shelly C.
Mato, José M.
Martínez-Chantar, María L.
Beraza, Naiara
Publication Title: 
Gastroenterology

BACKGROUND & AIMS: Patients with cirrhosis are at high risk for developing hepatocellular carcinoma (HCC), and their liver tissues have abnormal levels of S-adenosylmethionine (SAMe). Glycine N-methyltransferase (GNMT) catabolizes SAMe, but its expression is down-regulated in HCC cells. Mice that lack GNMT develop fibrosis and hepatomas and have alterations in signaling pathways involved in carcinogenesis. We investigated the role of GNMT in human HCC cell lines and in liver carcinogenesis in mice.

Author(s): 
Martínez-López, Nuria
García-Rodríguez, Juan L.
Varela-Rey, Marta
Gutiérrez, Virginia
Fernández-Ramos, David
Beraza, Naiara
Aransay, Ana M.
Schlangen, Karin
Lozano, Juan Jose
Aspichueta, Patricia
Luka, Zigmund
Wagner, Conrad
Evert, Matthias
Calvisi, Diego F.
Lu, Shelly C.
Mato, José M.
Martínez-Chantar, María L.
Publication Title: 
Hepatology (Baltimore, Md.)

Methionine adenosyltransferase 1A (MAT1A) and glycine N-methyltransferase (GNMT) are the primary genes involved in hepatic S-adenosylmethionine (SAMe) synthesis and degradation, respectively. Mat1a ablation in mice induces a decrease in hepatic SAMe, activation of lipogenesis, inhibition of triglyceride (TG) release, and steatosis. Gnmt-deficient mice, despite showing a large increase in hepatic SAMe, also develop steatosis.

Author(s): 
Martínez-Uña, Maite
Varela-Rey, Marta
Cano, Ainara
Fernández-Ares, Larraitz
Beraza, Naiara
Aurrekoetxea, Igor
Martínez-Arranz, Ibon
García-Rodríguez, Juan L.
Buqué, Xabier
Mestre, Daniela
Luka, Zigmund
Wagner, Conrad
Alonso, Cristina
Finnell, Richard H.
Lu, Shelly C.
Martínez-Chantar, M. Luz
Aspichueta, Patricia
Mato, José M.
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