Methionine Adenosyltransferase

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: 
Proceedings of the National Academy of Sciences of the United States of America

Recent work shows that S-adenosylmethionine (AdoMet) helps maintain normal liver function as chronic hepatic deficiency results in spontaneous development of steatohepatitis and hepatocellular carcinoma. The mechanisms by which these nontraditional functions of AdoMet occur are unknown. Here, we use knockout mice deficient in hepatic AdoMet synthesis (MAT1A(-/-)) to study the proteome of the liver during the development of steatohepatitis.

Author(s): 
Santamaría, Enrique
Avila, Matías A.
Latasa, M. Ujue
Rubio, Angel
Martín-Duce, Antonio
Lu, Shelly C.
Mato, José M.
Corrales, Fernando J.
Publication Title: 
The Journal of Biological Chemistry

In mammals, methionine adenosyltransferase (MAT), the enzyme responsible for S-adenosylmethionine (AdoMet) synthesis, is encoded by two genes, MAT1A and MAT2A. In liver, MAT1A expression is associated with high AdoMet levels and a differentiated phenotype, whereas MAT2A expression is associated with lower AdoMet levels and a dedifferentiated phenotype. In the current study, we examined regulation of MAT2A gene expression by l-methionine availability using HepG2 cells.

Author(s): 
Martínez-Chantar, María L.
Latasa, M. Ujue
Varela-Rey, Marta
Lu, Shelly C.
García-Trevijano, Elena R.
Mato, José M.
Avila, Matías A.
Publication Title: 
The Journal of Biological Chemistry

Two genes (MAT1A and MAT2A) encode for methionine adenosyltransferase (MAT), an essential cellular enzyme responsible for S-adenosylmethionine biosynthesis. MAT1A is expressed mostly in the liver, whereas MAT2A is widely distributed. We showed a switch from MAT1A to MAT2A expression in human hepatocellular carcinoma (HCC), which facilitates cancer cell growth. Using DNase I footprinting analysis, we previously identified a region in the MAT2A promoter protected from DNase I digestion in HCC.

Author(s): 
Yang, Heping
Sadda, Mamatha R.
Yu, Victor
Zeng, Ying
Lee, Taunia D.
Ou, Xiaopeng
Chen, Lixin
Lu, Shelly C.
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

The transsulfuration pathway converts homocysteine to cysteine and represents the metabolic link between antioxidant and methylation metabolism. The first and committing step in this pathway is catalyzed by cystathionine beta-synthase (CBS), which is subject to complex regulation, including allosteric activation by the methyl donor, S-adenosylmethionine (AdoMet).

Author(s): 
Prudova, Anna
Bauman, Zachary
Braun, Aaron
Vitvitsky, Victor
Lu, Shelly C.
Banerjee, Ruma
Publication Title: 
Hepatology (Baltimore, Md.)

Leptin is an adiopokine that plays a pivotal role in the progression of liver fibrogenesis and carcinogenesis. Recently, leptin was shown to be mitogenic in human liver cancer cell lines HepG2 and Huh7. Whether leptin can act as a mitogen in normal hepatocytes is unclear. Methionine adenosyltransferase (MAT) is an essential enzyme that catalyzes the formation of S-adenosylmethionine (SAMe), the principal methyl donor and precursor of polyamines.

Author(s): 
Ramani, Komal
Yang, Heping
Xia, Meng
Ara, Ainhoa Iglesias
Mato, José M.
Lu, Shelly C.
Publication Title: 
Gastroenterology

BACKGROUND & AIMS: Methionine adenosyltransferase (MAT) catalyzes S-adenosylmethionine biosynthesis. Two genes (MAT1A and MAT2A) encode for the catalytic subunit of MAT, while a third gene (MAT2beta) encodes for a regulatory subunit that modulates the activity of MAT2A-encoded isoenzyme. We uncovered multiple splicing variants while characterizing its 5'-flanking region. The aims of our current study are to examine the expression pattern, regulation, and functions of the 2 major variants: V1 and V2.

Author(s): 
Yang, Heping
Ara, Ainhoa Iglesias
Magilnick, Nathaniel
Xia, Meng
Ramani, Komal
Chen, Hui
Lee, Taunia D.
Mato, José M.
Lu, Shelly C.
Publication Title: 
Hepatology (Baltimore, Md.)

Methionine adenosyltransferase (MAT) is an essential enzyme that catalyzes the biosynthesis of S-adenosylmethionine. Hepatic MAT activity falls in chronic liver diseases, and mice lacking Mat1a are predisposed to liver injury and develop hepatocellular carcinoma (HCC) spontaneously by 18 months. The current work examined the hypothesis that liver cancer stem cells contribute to HCC in this model. Livers from 6- and 18-month-old Mat1a-knockout (KO) mice and their wild-type (WT) littermates were fractionated and isolated by flow cytometry.

Author(s): 
Rountree, C. Bart
Senadheera, Shantha
Mato, José M.
Crooks, Gay M.
Lu, Shelly C.
Publication Title: 
Laboratory Investigation; a Journal of Technical Methods and Pathology

Endotoxemia participates in the pathogenesis of many liver injuries. Lipopolysaccharide (LPS) was shown to inactivate hepatic methionine adenosyltransferase (MAT), the enzyme responsible for S-adenosylmethionine (SAMe) biosynthesis. SAMe treatment was shown to prevent the LPS-induced increase in tumor necrosis factor-alpha, which may be one of its beneficial effects. SAMe is also an important precursor of glutathione (GSH) and GSH was shown to ameliorate LPS-induced hepatotoxicity.

Author(s): 
Ko, Kwangsuk
Yang, Heping
Noureddin, Mazen
Iglesia-Ara, Ainhoa
Xia, Meng
Wagner, Conrad
Luka, Zigmund
Mato, José M.
Lu, Shelly C.
Publication Title: 
Gastroenterology

BACKGROUND & AIMS: Genomic instability participates in the pathogenesis of hepatocellular carcinoma (HCC). Apurinic/apyrimidinic endonuclease 1 (APEX1) participates in the base excision repair of premutagenic apurinic/apyrimidinic (AP) sites. Mice deficient in methionine adenosyltransferase 1a (Mat1a KO) have chronic hepatic deficiency of S-adenosylmethionine (SAMe) and increased oxidative stress, and develop HCC. We examined livers of Mat1a KO mice for genomic instability and dysregulation of APEX1.

Author(s): 
Tomasi, Maria Lauda
Iglesias-Ara, Ainhoa
Yang, Heping
Ramani, Komal
Feo, Francesco
Pascale, Maria Rosa
Martínez-Chantar, M. Luz
Mato, José M.
Lu, Shelly C.

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