Disease relevance of MAT1A

• We have reported a switch from MAT1A to MAT2A gene expression in human liver cancer cells [1].
• Hypermethylation of MAT1A promoter could participate in its reduced expression in cirrhosis [2].
• Clinical manifestations are variable and poorly understood, although a number of individuals with homozygous null mutations in MAT1A have neurological problems, including brain demyelination [3].
• Human hepatoma cell lines in which MAT1A is not expressed were also hypermethylated at this locus [4].
• Patients with alcoholic liver disease have decreased hepatic MAT activity owing to both decreased MAT1A expression and inactivation of the MAT1A-encoded isoenzymes, culminating in decreased SAMe biosynthesis [5].

Psychiatry related information on MAT1A

• Decreased methionine adenosyltransferase activity in erythrocytes of patients with dementia disorders [6].
• Influence of vitamin B12 on brain methionine adenosyltransferase activity in senile dementia of the Alzheimer's type [7].

High impact information on MAT1A

• The levels of MAT1A mRNA as well as MAT I/III protein decreased in cultured rat hepatocytes by in situ generation of ceramide from exogenous human placenta ASMase [8].
• Here we show that acidic sphingomyelinase (ASMase) mediates the downregulation of MAT1A by TNF-alpha [8].
• Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency [9].
• We recently demonstrated that apoptosis was prominent in undifferentiated cells around dysplastic tubules (Winyard, P.J.D., J. Nauta, D.S. Lirenman, P. Hardman, V.R. Sams, R.A. Risdon, and A.S. Woolf. 1996. Kidney Int. 49:135-146), perhaps explaining the tendency of some of these organs to regress [10].
• We investigated sulfur and methyl group metabolism in a 31-yr-old man with partial hepatic methionine adenosyltransferase (MAT) deficiency [11].

Chemical compound and disease context of MAT1A

• Two patients-a compound heterozygote for truncating and severely inactivating missense mutations and a homozygote for an aberrant splicing MAT1A mutation-have plasma methionine in the 1,226-1,870 microM range (normal 5-35 microM) and manifest abnormalities of the brain gray matter or signs of brain demyelination [3].
• Finally we demonstrate that MAT1A expression is reactivated in the human hepatoma cell line HepG2 treated with 5-aza-2'-deoxycytidine or the histone deacetylase inhibitor trichostatin, suggesting a role for DNA hypermethylation and histone deacetylation in MAT1A silencing [4].
• Role of methionine adenosyltransferase and S-adenosylmethionine in alcohol-associated liver cancer [5].
• Treatment with ethionine and seleno-D,L-ethionine, two inhibitors known to have I50 values 50 to 60 times lower against SAMS purified from Novikoff hepatoma cells as compared with SAMS purified from normal rat liver, resulted in increased cell lysis in HepG2 and HuH-7 cells but not cultured rat hepatocytes [12].
• OBJECTIVE: To evaluate the impact of weekly treatment with ferrous sulfate on hemoglobin level, morbidity and nutritional status in a sample of anemic infants from Zona da Mata Meridional in the state of Pernambuco, Brazil [13].

Biological context of MAT1A

• Cell growth and DNA synthesis rates were reduced by approximately 20-25% after transfection with MAT1A and by an additional 30-40% after MAT2A antisense treatment [1].
• Methylation of MAT1A promoter was assessed by methylation-sensitive restriction enzyme digestion of genomic DNA [2].
• We showed a switch from MAT1A to MAT2A expression in human liver cancer, which facilitates cancer cell growth [14].
• Molecular genetic studies demonstrate that each patient is a compound heterozygote for two mutations in MAT1A, the gene that encodes the catalytic subunit that composes MAT I and MAT III: a previously known inactivating G378S point mutation, and a novel W387X truncating mutation [15].
• We have characterized 10 MAT1A mutations in MAT I/III-deficient individuals and shown that the associated hypermethioninemic phenotype was inherited as an autosomal recessive trait [16].

Anatomical context of MAT1A

• The human MAT1A promoter was able to efficiently drive luciferase expression in Chang cells, a human liver cell line, but not in HeLa cells [17].
• Our data indicate that MAT1A promoter is hypomethylated in liver and hypermethylated in kidney and fetal rat hepatocytes, indicating that this modification is tissue specific and developmentally regulated [4].
• The role of c-Myb in the up-regulation of methionine adenosyltransferase 2A expression in activated Jurkat cells [18].
• Since the hepatic and fibroblast isoenzymes of methionine adenosyltransferase differ in their genetic control, this family's biochemical findings appear consistent with a mutation in the structural gene for the hepatic methionine adenosyltransferase isoenzyme [19].
• The increased methionine was not associated with deficiency of methionine adenosyltransferase, which was normal or increased in liver, muscle, erythrocytes, and cultured fibroblasts [20].

Associations of MAT1A with chemical compounds

• SAM level and SAM:S-adenosylhomocysteine (SAH) ratio increased by 50-75% after MAT1A transfection and by an additional 60-80% after MAT2A antisense treatment [1].
• Two genes (MAT1A and MAT2A) encode for methionine adenosyltransferase (MAT), an essential cellular enzyme responsible for S-adenosylmethionine biosynthesis [21].
• Methionine adenosyltransferase (MAT) I/III deficiency, caused by mutations in the MAT1A gene, is characterized by persistent hypermethioninemia without elevated homocysteine or tyrosine [3].
• Here we show that the only mutation uncovered in one of these families, G, is a G-->A transition at nt 791 in exon VII of one MAT1A allele that converts an arginine at position 264 to a histidine (R264H) [16].
• This change yields a MAT1A-encoded subunit in which arginine 264 is replaced by histidine [22].

Regulatory relationships of MAT1A

• Isoform 1 is up-regulated in the serum of MAT1A(-/-) mice much earlier than any histological manifestation of liver disease [23].

Other interactions of MAT1A

• Regulation of the human MAT2B gene encoding the regulatory beta subunit of methionine adenosyltransferase, MAT II [24].
• Induction of human methionine adenosyltransferase 2A expression by tumor necrosis factor alpha. Role of NF-kappa B and AP-1 [21].
• Methionine loading of two affected family members revealed a diminished ability to catabolize methionine, but the activities of methionine adenosyltransferase and cystathionine beta-synthase were not decreased in fibroblasts from four affected family members [19].
• Three down-regulated metabolic enzymes, methionine adenosyltransferase, glycine N-methyltransferase, and betaine-homocysteine S-methyltransferase that are involved in the methylation cycle in the liver are of special interest [25].
• In the present work, we have attempted a comprehensive analysis of proteins associated with hepatocarcinogenesis in MAT1A knock out mice using a combination of two-dimensional electrophoresis and mass spectrometry, to then apply the resulting information to identify hallmarks of human HCC [26].

Analytical, diagnostic and therapeutic context of MAT1A

• In the present work we examined MAT1A promoter methylation status by means of methylation sensitive restriction enzyme analysis [4].
• Immunoprecipitation of mononucleosomes from liver and kidney tissues with antibodies mainly specific to acetylated histone H4 and subsequent Southern blot analysis with a MAT1A promoter probe demonstrated that MAT1A expression is linked to elevated levels of chromatin acetylation [4].
• SAMS mRNAs were localized by in situ hybridization at the endocarp of developing fruits and in the ovules of senescing ovaries [27].
• Northern blot analysis showed that while normal liver expresses only liver-specific SAMS, both HepG2 and HuH-7 cells express only nonliver-specific SAMS [12].
• To explore the roles of three aspartate residues, Asp88, Asp130, and Asp274, found in the proposed inducer binding site of lac repressor [Sams, C. F., Vyas, N. K., Quiocho, F. A., & Matthews, K. S. (1984) Nature 310, 429-430], each site was substituted with alanine, glutamate, lysine, or asparagine by site-specific mutagenesis [28].

References