Limits...
Role of methionine adenosyltransferase genes in hepatocarcinogenesis.

Ramani K, Mato JM, Lu SC - Cancers (Basel) (2011)

Bottom Line: Methionine adenosyltransferase (MAT) is an essential enzyme required for the biosynthesis of S-adenosylmethionine (AdoMet), an important methyl donor in the cell.Alterations in the expression of MAT genes and a decline in AdoMet biosynthesis are known to be associated with liver injury, cirrhosis and HCC.This review focuses on the role of MAT genes in HCC development and the scope for therapeutic strategies using these genes.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, Southern California Research Center for Alcoholic Liver and Pancreatic Diseases & Cirrhosis, Keck School of Medicine USC, Los Angeles, California 90033, USA. shellylu@usc.edu.

ABSTRACT
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Detection of HCC can be difficult, as most of the patients who develop this tumor have no symptoms other than those related to their longstanding liver disease. There is an urgent need to understand the molecular mechanisms that are responsible for the development of this disease so that appropriate therapies can be designed. Methionine adenosyltransferase (MAT) is an essential enzyme required for the biosynthesis of S-adenosylmethionine (AdoMet), an important methyl donor in the cell. Alterations in the expression of MAT genes and a decline in AdoMet biosynthesis are known to be associated with liver injury, cirrhosis and HCC. This review focuses on the role of MAT genes in HCC development and the scope for therapeutic strategies using these genes.

No MeSH data available.


Related in: MedlinePlus

Methionine metabolism in liver. The first step in methionine metabolism is catalyzed by methionine adenosyltransferase (MAT), generating S-adenosylmethionine (AdoMet), which is converted to AdoHcy during transmethylation reactions. AdoHcy hydrolase catalyzes the reversible hydrolysis of AdoHcy to yield homocysteine and adenosine. In the liver, homocysteine can undergo three metabolic pathways (labeled as 1, 2 and 3). First is the transsulfuration pathway, which converts homocysteine to cysteine through a two-step process consisting of two vitamin B6 dependent enzymes, cystathionine β-synthase (CBS) and γ-cystathionase. Cysteine is further utilized for biosynthesis of GSH. The other two pathways that metabolize homocysteine re-synthesize methionine from homocysteine. One is catalyzed by methionine synthase (MS) and the other is catalyzed by betaine homocysteine methyltransferase (BHMT). Remethylation of homocysteine via MS requires 5-methyltetrahydrofolate (5-MTHF), which is derived from 5,10-methylenetetrahydrofolate (5,10-MTHF) in a reaction catalyzed by methylenetetrahydrofolate reductase (MTHFR). 5-MTHF is then converted to tetrahydrofolate (THF) as it donates its methyl group and THF is converted to 5,10-MTHF to complete the folate cycle. AdoMet is also utilized in the synthesis of polyamines, thereby generating methylthioadenosine (MTA) [9].
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3757373&req=5

f1-cancers-03-01480: Methionine metabolism in liver. The first step in methionine metabolism is catalyzed by methionine adenosyltransferase (MAT), generating S-adenosylmethionine (AdoMet), which is converted to AdoHcy during transmethylation reactions. AdoHcy hydrolase catalyzes the reversible hydrolysis of AdoHcy to yield homocysteine and adenosine. In the liver, homocysteine can undergo three metabolic pathways (labeled as 1, 2 and 3). First is the transsulfuration pathway, which converts homocysteine to cysteine through a two-step process consisting of two vitamin B6 dependent enzymes, cystathionine β-synthase (CBS) and γ-cystathionase. Cysteine is further utilized for biosynthesis of GSH. The other two pathways that metabolize homocysteine re-synthesize methionine from homocysteine. One is catalyzed by methionine synthase (MS) and the other is catalyzed by betaine homocysteine methyltransferase (BHMT). Remethylation of homocysteine via MS requires 5-methyltetrahydrofolate (5-MTHF), which is derived from 5,10-methylenetetrahydrofolate (5,10-MTHF) in a reaction catalyzed by methylenetetrahydrofolate reductase (MTHFR). 5-MTHF is then converted to tetrahydrofolate (THF) as it donates its methyl group and THF is converted to 5,10-MTHF to complete the folate cycle. AdoMet is also utilized in the synthesis of polyamines, thereby generating methylthioadenosine (MTA) [9].

Mentions: The liver is the main source of biosynthesis and consumption of the principle biological methyl donor, S-adenosylmethionine (AdoMet, also often abbreviated as SAMe and SAM). The synthesis of AdoMet from methionine and ATP is catalyzed by MAT isoenzymes. AdoMet is also a precursor for polyamine biosynthesis and in hepatocytes, a precursor for cysteine, the rate-limiting amino acid for the synthesis of the antioxidant glutathione (GSH) (Figure 1) [9]. Under normal physiological conditions, most of the AdoMet is utilized in transmethylation reactions and is converted to S-adenosylhomocysteine (AdoHcy, often abbreviated as SAH) (Figure 1) [10]. AdoHcy is a potent competitive inhibitor of transmethylation reactions. Both an increase in AdoHcy level and a decrease in the AdoMet:AdoHcy ratio are known to inhibit transmethylation reactions [9]. For this reason, the removal of AdoHcy is essential. The reaction that converts AdoHcy to homocysteine and adenosine is reversible and catalyzed by AdoHcy hydrolase [10]. The thermodynamics of this reaction favor the synthesis of AdoHcy. In vivo, the reaction proceeds in the direction of hydrolysis only if the products, adenosine and homocysteine, are rapidly removed [10].


Role of methionine adenosyltransferase genes in hepatocarcinogenesis.

Ramani K, Mato JM, Lu SC - Cancers (Basel) (2011)

Methionine metabolism in liver. The first step in methionine metabolism is catalyzed by methionine adenosyltransferase (MAT), generating S-adenosylmethionine (AdoMet), which is converted to AdoHcy during transmethylation reactions. AdoHcy hydrolase catalyzes the reversible hydrolysis of AdoHcy to yield homocysteine and adenosine. In the liver, homocysteine can undergo three metabolic pathways (labeled as 1, 2 and 3). First is the transsulfuration pathway, which converts homocysteine to cysteine through a two-step process consisting of two vitamin B6 dependent enzymes, cystathionine β-synthase (CBS) and γ-cystathionase. Cysteine is further utilized for biosynthesis of GSH. The other two pathways that metabolize homocysteine re-synthesize methionine from homocysteine. One is catalyzed by methionine synthase (MS) and the other is catalyzed by betaine homocysteine methyltransferase (BHMT). Remethylation of homocysteine via MS requires 5-methyltetrahydrofolate (5-MTHF), which is derived from 5,10-methylenetetrahydrofolate (5,10-MTHF) in a reaction catalyzed by methylenetetrahydrofolate reductase (MTHFR). 5-MTHF is then converted to tetrahydrofolate (THF) as it donates its methyl group and THF is converted to 5,10-MTHF to complete the folate cycle. AdoMet is also utilized in the synthesis of polyamines, thereby generating methylthioadenosine (MTA) [9].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757373&req=5

f1-cancers-03-01480: Methionine metabolism in liver. The first step in methionine metabolism is catalyzed by methionine adenosyltransferase (MAT), generating S-adenosylmethionine (AdoMet), which is converted to AdoHcy during transmethylation reactions. AdoHcy hydrolase catalyzes the reversible hydrolysis of AdoHcy to yield homocysteine and adenosine. In the liver, homocysteine can undergo three metabolic pathways (labeled as 1, 2 and 3). First is the transsulfuration pathway, which converts homocysteine to cysteine through a two-step process consisting of two vitamin B6 dependent enzymes, cystathionine β-synthase (CBS) and γ-cystathionase. Cysteine is further utilized for biosynthesis of GSH. The other two pathways that metabolize homocysteine re-synthesize methionine from homocysteine. One is catalyzed by methionine synthase (MS) and the other is catalyzed by betaine homocysteine methyltransferase (BHMT). Remethylation of homocysteine via MS requires 5-methyltetrahydrofolate (5-MTHF), which is derived from 5,10-methylenetetrahydrofolate (5,10-MTHF) in a reaction catalyzed by methylenetetrahydrofolate reductase (MTHFR). 5-MTHF is then converted to tetrahydrofolate (THF) as it donates its methyl group and THF is converted to 5,10-MTHF to complete the folate cycle. AdoMet is also utilized in the synthesis of polyamines, thereby generating methylthioadenosine (MTA) [9].
Mentions: The liver is the main source of biosynthesis and consumption of the principle biological methyl donor, S-adenosylmethionine (AdoMet, also often abbreviated as SAMe and SAM). The synthesis of AdoMet from methionine and ATP is catalyzed by MAT isoenzymes. AdoMet is also a precursor for polyamine biosynthesis and in hepatocytes, a precursor for cysteine, the rate-limiting amino acid for the synthesis of the antioxidant glutathione (GSH) (Figure 1) [9]. Under normal physiological conditions, most of the AdoMet is utilized in transmethylation reactions and is converted to S-adenosylhomocysteine (AdoHcy, often abbreviated as SAH) (Figure 1) [10]. AdoHcy is a potent competitive inhibitor of transmethylation reactions. Both an increase in AdoHcy level and a decrease in the AdoMet:AdoHcy ratio are known to inhibit transmethylation reactions [9]. For this reason, the removal of AdoHcy is essential. The reaction that converts AdoHcy to homocysteine and adenosine is reversible and catalyzed by AdoHcy hydrolase [10]. The thermodynamics of this reaction favor the synthesis of AdoHcy. In vivo, the reaction proceeds in the direction of hydrolysis only if the products, adenosine and homocysteine, are rapidly removed [10].

Bottom Line: Methionine adenosyltransferase (MAT) is an essential enzyme required for the biosynthesis of S-adenosylmethionine (AdoMet), an important methyl donor in the cell.Alterations in the expression of MAT genes and a decline in AdoMet biosynthesis are known to be associated with liver injury, cirrhosis and HCC.This review focuses on the role of MAT genes in HCC development and the scope for therapeutic strategies using these genes.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, Southern California Research Center for Alcoholic Liver and Pancreatic Diseases & Cirrhosis, Keck School of Medicine USC, Los Angeles, California 90033, USA. shellylu@usc.edu.

ABSTRACT
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Detection of HCC can be difficult, as most of the patients who develop this tumor have no symptoms other than those related to their longstanding liver disease. There is an urgent need to understand the molecular mechanisms that are responsible for the development of this disease so that appropriate therapies can be designed. Methionine adenosyltransferase (MAT) is an essential enzyme required for the biosynthesis of S-adenosylmethionine (AdoMet), an important methyl donor in the cell. Alterations in the expression of MAT genes and a decline in AdoMet biosynthesis are known to be associated with liver injury, cirrhosis and HCC. This review focuses on the role of MAT genes in HCC development and the scope for therapeutic strategies using these genes.

No MeSH data available.


Related in: MedlinePlus