Disease relevance of Mat1a

• Hypoxia dramatically reduced methionine adenosyltransferase gene transcription, and messenger stability was also decreased, although to a lesser extent [1].
• The effect of AdoMet on okadaic acid (OA)-induced apoptosis was evaluated using primary cultures of rat hepatocytes and human hepatoma cell lines [2].
• AdoMet administration attenuates experimental liver damage, improves survival of alcoholic patients with cirrhosis, and prevents experimental hepatocarcinogenesis [2].
• The results show that intravenously administered AdoMet is efficiently metabolized in vivo up to the highest tested dose (250 mumol X kg-1 body weight), about two-thirds of the metabolized compound being utilized via transmethylation and cleavage to methylthioadenosine and one-third via decarboxylation [3].
• Renal ischemia for 30min resulted in an increase of AdoHcy levels from 0.7+/-0.05 to 9.1+/-0.6nmol/g wet weight and in a dramatic decrease of the AdoMet/AdoHcy ratio and energy charge from 65.1+/-5.6 to 2.8+/-0.2 and from 0.87+/-0.01 to 0.25+/-0.01, respectively [4].

High impact information on Mat1a

• The enzyme catalyses the transfer of the methyl group from S-adenosyl-L-methionine (AdoMet) to one hydroxyl group of catechols [5].
• Precursor availability for AdoMet was limited when rats were fed a low methionine diet [6].
• It is reasoned that perturbation of a second regulatory element in polyamine biosynthesis, i.e., the generation of propylamine groups from S-adenosylmethionine (AdoMet), would potentiate the effectiveness of DFMO [6].
• Selenite, another effective chemopreventive agent in this tumor model, also requires AdoMet for its metabolism [6].
• S-adenosylmethionine (AdoMet) synthesis by methionine adenosyltransferase is the first step in methionine metabolism, and NO regulates hepatocyte S-adenosylmethionine levels through specific inhibition of this enzyme [7].

Chemical compound and disease context of Mat1a

• Adduct 14 was a potent inhibitor of the rat M-2 (normal tissue) and M-T (Novikoff ascitic hepatoma) variants of methionine adenosyltransferase and gave competitive kinetics vs MgATP (Ki = 0.39 and 0.63 microM, respectively) or vs L-methionine (Ki = 2.2 and 2.7 microM) [8].
• Therefore, the present investigation was performed to assess changes of renal AdoHcy and AdoMet tissue contents during ischemia and after administration of adenosine and homocysteine or both in the ischemic rat kidney [4].
• Hepatic deficiency of S-adenosylmethionine (AdoMet) is a critical acquired metabolic abnormality in alcoholic liver disease (ALD) and in many experimental models of hepatotoxicity [9].
• The agents studied are curative for African trypanosomiasis infections, either clinically (DFMO) or in model infections (MDL 73811, sinefungin) and thus highlight interference with AdoMet metabolism and methylation reactions as biochemical consequences of these agents [10].
• The normethyl analog of AdoMet, S-adenosylhomocysteine, did not cause hypokinesia or tremors, but it blocked the AdoMet-induced motor effects [11].

Biological context of Mat1a

• NO-mediated inactivation and transcriptional arrest seem to be the two major pathways by which oxygen levels control hepatic methionine adenosyltransferase, the enzyme necessary for methylation reactions and for the synthesis of polyamines and glutathione [1].
• CONCLUSIONS: We have established the molecular basis for the regulation of methionine adenosyltransferase activity and gene expression by hypoxia [1].
• Interestingly, AdoMet and MTA did not protect HuH7 cells from OA-induced apoptosis; conversely both compounds behaved as proapoptotic agents [2].
• Liver cell proliferation requires methionine adenosyltransferase 2A mRNA up-regulation [12].
• The exogenous concentration of methionine did not alter the hepatic concentration of AdoHcy (8 to 20 nmol/g) while adenosine or homocysteine blocked hydrolysis of AdoHcy resulting in elevated levels of AdoHcy (400 to 600 nmol/g) and AdoMet (300 to 600 nmol/g) [13].

Anatomical context of Mat1a

• Recombinant rat liver methionine adenosyltransferase has been refolded into fully active tetramers (MAT I) and dimers (MAT III), using as a source chaotrope-solubilized aggregates resulting from specific washes of inclusion bodies [14].
• RESULTS: Methionine adenosyltransferase was inactivated in hepatocytes kept under low oxygen levels [1].
• The activity of the enzyme that synthesizes SAM, methionine adenosyltransferase (MAT), increases 2.5-fold at night in the pineal gland [15].
• Experiments utilizing rat granulosa cells transfected with luciferase reporter genes driven by the 5'-flanking region of the rLHR gene demonstrate a functional role for the SAS site in the cAMP responsiveness of the rLHR gene [16].
• 3. The decline in skeletal-muscle AdoMet decarboxylase activity in response to spermidine may be due to an increased rate of degradation of the enzyme protein [17].

Associations of Mat1a with chemical compounds

• Methionine adenosyltransferase is a ubiquitous enzyme that catalyzes the only known route of biosynthesis of S-adenosylmethionine, the major methyl group donor in cell metabolism [18].
• Blockage of dimer-tetramer interconversion has been found related to the production of a single intramolecular disulfide in methionine adenosyltransferase during the GSH/GSSG folding process [14].
• Rat liver methionine adenosyltransferase incorporated 8 mol of N-ethylmaleimide per mol of subunit upon denaturation in the presence of 8 M urea, whereas 10 such groups were labelled when dithiothreitol was also included [19].
• Hypoxia induced the expression of nitric oxide (NO) synthase, and the inactivation of methionine adenosyltransferase was prevented by the NO synthase inhibitor N(G)-monomethyl-L-arginine methyl ester [1].
• Protein arginine methyltransferases (PRMTs) mediate the AdoMet-dependent methylation of many proteins, including many RNA binding proteins involved in various aspects of RNA processing and/or transport [20].

Physical interactions of Mat1a

• The crystal structure of GNMT complexed with AdoMet and acetate, a competitive inhibitor of glycine, has been determined at 2.2 A resolution [21].
• An equilibrium binding study shows that guanidinoacetate methyltransferase in the free form binds AdoMet but not guanidinoacetate [22].

Enzymatic interactions of Mat1a

• Glycine N-methyltransferase (GNMT) from rat liver is a tetrameric enzyme with 292 amino acid residues in each identical subunit and catalyzes the S-adenosylmethionine (AdoMet) dependent methylation of glycine to form sarcosine [21].

Regulatory relationships of Mat1a

• Although guanidinoacetate methyltransferase is irreversibly inactivated upon ultraviolet irradiation in the absence of AdoMet, the enzyme inactivated by 1-h exposure to ultraviolet irradiation has been shown to bind AdoMet with an affinity identical to that of the native enzyme [23].
• Interleukin-2 (IL-2) stimulates the induction of this gene expression and AdoMet synthetase activity in G1 lymphoblasts, in part by an increase in the transcription rate of the gene [24].

Other interactions of Mat1a

• The AdoMet-GNMT structure served as the starting model [25].
• ODC activity and AdoMet DC activity were induced by those selenium compounds that also increased liver selenium content, but the magnitude of enzyme induction by those compounds was not correlated with the hepatic concentration of total selenium determined fluorometrically [26].
• The activities of methionine adenosyltransferase (MAT), cystathionine beta-synthase (CbetaS) and cystathionine gamma-lyase (CgammaL) were all inhibited [27].
• When rats were fed a 10% casein diet containing 2% methionine, the activities of methionine adenosyltransferase, cystathionine beta-synthase, and cystathionine gamma-lyase, which participate in the methionine metabolism in the transsulfuration pathway, were significantly enhanced [28].
• Rat guanidinoacetate methyltransferase has two aspartate residues (Asp-129 and Asp-134) conforming to the motif in close proximity to Tyr-136 that is photoaffinity-labeled by AdoMet (Takata, Y., and Fujioka, M. (1992) Biochemistry 31, 4369-4374) [29].

Analytical, diagnostic and therapeutic context of Mat1a

• Intraperitoneal infusion of 400 microg of R-(+) nicotine kg(-1) h(-1) intraperitoneal for 21 days caused a 15-fold reduction in lung AdoMet although neither plasma nor liver were changed [30].
• To assess the possible functional role of GNMT phosphorylation, the effect of okadaic acid on hepatocytic AdoMet and AdoHcy levels was examined, using HPLC separation for metabolite analysis [31].
• Intraperitoneal injection of ethionine to male rats for up to 12 days caused a pronounced fall in S-adenosylmethionine (AdoMet) in liver, but did not or only slightly affect AdoMet in kidney and spleen [32].
• High-performance liquid chromatography of this peptide after acid hydrolysis and phenyl isothiocyanate derivatization suggests that the entire molecule of AdoMet is attached to Tyr-136 [23].
• The reversible unfolding of rat liver methionine adenosyltransferase dimer by urea under equilibrium conditions has been monitored by fluorescence spectroscopy, CD, size-exclusion chromatography, analytical ultracentrifugation and enzyme activity measurements [33].

References