Specific loss of the high-molecular-weight form of S -adenosyl-l-methionine synthetase in human liver cirrhosis

Cabrero, Carmen; Duce, Antonio Martín; Ortiz, Pablo; Alemany, Susana; Mato, José M.

doi:10.1002/hep.1840080610

Cited by 162 publications

(88 citation statements)

References 18 publications

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“…15,[32][33][34][35][36][37] Inhibition of the liver-specific MAT by 50% to 60% was felt to be the explanation for hypermethioninemia and delayed plasma clearance of methionine after intravenous injection in cirrhotic patients. 32,33,38,39 With the exception of hypoxia, in which a decreased MAT1A mRNA level was found, 35,37 all of the other examples of decreased liver-specific MAT activity reflected inactivation of the enzyme without alteration in the protein 15,16 or mRNA levels. 1,34,40 The molecular mechanism of the inactivation of liver-specific MAT has been recently elucidated.…”

Section: Discussionmentioning

confidence: 99%

Differential Effect of Thioacetamide on Hepatic Methionine Adenosyltransferase Expression in the Rat

Huang¹,

Mato

Kanel

et al. 1999

Hepatology

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Liver-specific and non-liver-specific methionine adenosyltransferase (MAT) are products of two genes, MAT1A and MAT2A, respectively, that catalyze the formation of S-adenosylmethionine (SAM), the principal methyl donor. Mature liver expresses mainly MAT1A. We showed a switch from MAT1A to MAT2A gene expression in human liver cancer cells that may offer a growth advantage. To gain a better understanding of the chronology and significance of the change in MAT expression, we examined changes in hepatic MAT expression after acute treatment of rats with a hepatocarcinogen, thioacetamide (TAA). TAA treatment for 3 weeks did not change the MAT1A mRNA level but reduced the liver-specific MAT protein level to below 30% of control. TAA also acutely reduced the activity of liverspecific MAT when added to normal liver homogenates. In contrast, both the mRNA and protein levels of non-liverspecific MAT were induced. Because liver-specific MAT exhibits a much higher Methionine adenosyltransferase (MAT) is a critical cellular enzyme that catalyzes the formation of S-adenosylmethionine (SAM), the principal biological methyl donor and the ultimate source of the propylamine moiety used in polyamine biosynthesis. 1,2 In mammals, two different genes, MAT1A and MAT2A, encode for two homologous MAT catalytic subunits, ␣1 and ␣2. 3-5 MAT1A is expressed only in liver, and it encodes the ␣1 subunit found in two native MAT isozymes, which are either a dimer (MAT III) or tetramer (MAT I) of this single subunit. 5 MAT2A is widely distributed. 3-5 MAT2A also predominates in the fetal liver and is progressively replaced by MAT1A during development. 6,7 MAT2A encodes for a catalytic subunit (␣2) found in a native MAT isozyme (MAT II), which is associated with a catalytically inactive regulatory subunit (␤) in lymphocytes encoded by yet a third unknown gene. 5,8 This regulatory ␤ subunit may be unique to lymphocytes, because it is not found in the kidney. 8 Different isoforms of MAT differ in kinetic and regulatory properties and responsiveness to sulfhydryl agents and dimethyl sulfoxide (DMSO). 2,9-13 The kinetic parameters varied in different studies depending on the purification procedure used and the purity of the enzyme. The K m for methionine is lowest for MAT II (Ϸ4-10 µmol/L), intermediate for MAT I (23 µmol/L-1 mmol/L), and highest for MAT III (215 µmol/L-7 mmol/L), with different studies reporting different absolute values. [9][10][11][12][13] The activity of MAT is also modulated by SAM, the product of the reaction it catalyzes. SAM strongly inhibits MAT II (IC 50 ϭ 60 µmol/L), whereas it minimally inhibits MAT I (IC 50 ϭ 400 µmol/L) and stimulates MAT III (up to eightfold at 500 µmol/L SAM). 10 In terms of responsiveness to sulfhydryl-modifying agents, the activity of liverspecific MAT is inhibited when certain critical cysteine residues of the enzyme are covalently modified. 1,11,[14][15][16] Modifications of these critical cysteine residues can inactivate the enzyme by direct interference with the substrate binding site(s) or by c...

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Section: Discussionmentioning

confidence: 99%

Differential Effect of Thioacetamide on Hepatic Methionine Adenosyltransferase Expression in the Rat

Huang¹,

Mato

Kanel

et al. 1999

Hepatology

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“…Normal higher levels of SAMe are required to maintain the normal liver metabolic state but lower levels of SAMe produced by MAT II mediates a control switch that regulates liver function 150 that results in cell proliferation. It is known that choline deficiency causes liver fibrosis and cirrhosis as well as decreased levels of S-adenosylmethionine 165,166 . It is also known that enhanced iNOS expression occurs in liver cirrhosis [167][168][169][170] .…”

Section: S-nitrosylation Of Liver Methionine Adenosyltransferasementioning

confidence: 99%

Nitric Oxide and Cancer Development

et al. 2007

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Abstract:The role of nitric oxide (NO) in cancer development has become a very active research area. This review presents an overview of many studies that implicate an important role of NO in the development of cancer. These include results in experimental models as well as many observations made on NO and inducible nitric oxide synthase (iNOS) in human cancers. Our survey of the literature has allowed us to conclude that in general large levels of NO will kill cancer cells but paradoxically at intermediate to lower levels NO prevents cancer cell apoptosis and enhances tumor growth. This basic tenet has been demonstrated in many experimental models. The mechanistic basis of how intermediate levels of NO mediate tumor development is an active area of research and is the subject of this review. NO mediated S-nitrosylation of key enzymes and regulatory proteins plays a critical role. Key proteins S-nitrosylated which enhance tumor development include several caspases involved in apoptosis, PTEN the tumor suppressor protein, Bcl-2 the mitochondrial protein which protects from apoptosis, OGG1 the DNA repair protein and methionine adenosyl transferase the liver protein which synthesizes adenosylmethionine. The S-nitrosylation of these proteins enhances DNA mutations, prevents cancer cell apoptosis and enhances oncogenic cell growth. (J Toxicol Pathol 2007; 20: 77-92)

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“…An important consequence of chronic alcohol abuse is abnormal metabolism of hepatic Sadenosylmethionine (SAMe) due to decreased hepatic methionine adenosyl transferase (MAT -MAT I) expression and activity, resulting in hepatic SAMe deficiency and hepatotoxicity (22). However, the effects of ethanol on non-hepatic MAT (MAT II) and SAMe levels in T lymphocytes have not been examined.…”

Section: Introductionmentioning

confidence: 99%

Ethanol inhibits methionine adenosyltransferase II activity and S-adenosylmethionine biosynthesis and enhances caspase-3-dependent cell death in T lymphocytes: relevance to alcohol-induced immunosuppression

Hote¹,

Sahoo²,

Jani³

et al. 2008

The Journal of Nutritional Biochemistry

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An important aspect in alcohol abuse associated immune suppression is the loss of T helper CD4 + lymphocytes leading to an impairment of multiple immune functions. Our work has shown that ethanol can sensitize CD4 + T lymphocytes to activation-induced, caspase-3 dependent cell death (AICD). It has been demonstrated that formation of S-adenosylmethionine (SAMe) catalyzed by methionine adenosyltransferase II (MAT II) is essential for CD4 + T cell activation and proliferation. Since ethanol is known to affect SAMe metabolism in hepatocytes, we investigated the effect of ethanol on MAT II activity/expression, SAMe biosynthesis and cell survival in CD4 + T lymphocytes. We demonstrate for the first time that ethanol at a physiologically relevant concentration (25mM) substantially decreased the enzymatic activity of MAT II in T lymphocytes. Ethanol was observed to decrease the transcription of MAT2A, which encodes the catalytic subunit of MAT II and is vital for MAT II activity and SAMe biosynthesis. Further, correspondent to its effect on MAT II, ethanol decreased intracellular SAMe levels and enhanced caspase-3 dependent AICD. Importantly, restoration of intracellular SAMe levels by exogenous SAMe supplementation considerably decreased both caspase-3 activity and apoptotic death in T lymphocytes. In conclusion, our data shows that MAT II and SAMe are critical molecular components essential for CD4 + T cell survival which are affected by ethanol leading to enhanced Address correspondence to: Shirish Barve PhD, Professor, Department of Medicine, Pharmacology and Toxicology, University of Louisville Medical Center, 511 S. Floyd, MDR Bldg., Rm#526, Louisville, KY 40202. Tel. 502 852 -5245; Fax. 502 562 -4271; shirish.barve@louisville.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AICD. Furthermore, these studies provide a clinical paradigm for the development of the much needed therapy using SAMe supplementation in the treatment of immune dysfunction induced by alcohol abuse. HHS Public Access

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Specific loss of the high-molecular-weight form of S -adenosyl-l-methionine synthetase in human liver cirrhosis

Cited by 162 publications

References 18 publications

Differential Effect of Thioacetamide on Hepatic Methionine Adenosyltransferase Expression in the Rat

Differential Effect of Thioacetamide on Hepatic Methionine Adenosyltransferase Expression in the Rat

Nitric Oxide and Cancer Development

Ethanol inhibits methionine adenosyltransferase II activity and S-adenosylmethionine biosynthesis and enhances caspase-3-dependent cell death in T lymphocytes: relevance to alcohol-induced immunosuppression

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