Methionine Adenosyltransferase 2A/2B and Methylation: Gene Sequence Variation and Functional Genomics

Nordgren, Kendra K. S.; Peng, Yi; Pelleymounter, Linda L.; Moon, Irene; Abo, Ryan; Feng, QiPing; Eckloff, Bruce W.; Yee, Vivien C.; Wieben, Eric D.; Weinshilboum, Richard M.

doi:10.1124/dmd.111.040857

Cited by 22 publications

(20 citation statements)

References 41 publications

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“…1) that had been published for these same 286 liver biopsy samples (Nordgren et al 2011, Feng et al 2011, Zhang et al 2009). BHMT was not expressed in the LCLs, but mRNA expression for the important methyltransferase enzyme COMT was significantly correlated with SHMT2 mRNA expression in those cells (p=3.20E-11, r=0.38).…”

Section: Resultsmentioning

confidence: 99%

Serine hydroxymethyltransferase 1 and 2: gene sequence variation and functional genomic characterization

Hebbring

Chai

et al. 2012

Journal of Neurochemistry

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Serine hydroxymethyltransferase (SHMT) catalyzes the transfer of a beta carbon from serine to tetrahydrofolate (THF) to form glycine and 5,10-methylene-THF. This reaction plays an important role in neurotransmitter synthesis and metabolism. We set out to resequence SHMT1 and SHMT2, followed by functional genomic studies. We identified 87 and 60 polymorphisms in SHMT1 and SHMT2, respectively. We observed no significant functional effect of the 13 nonsynonymous SNPs in these genes, either on catalytic activity or protein quantity. We imputed additional variants across the two genes using “1000 Genomes” data, and identified 14 variants that were significantly associated (p-value < 1.0E-10) with SHMT1 mRNA expression in lymphoblastoid cell lines. Many of these SNPs were also significantly correlated with basal SHMT1 protein expression in 268 human liver biopsy samples. Reporter gene assays suggested that the SHMT1 promoter SNP, rs669340, contributed to this variation. Finally, SHMT1 and SHMT2 expression were significantly correlated with those of other Folate and Methionine Cycle genes at both the mRNA and protein levels. These experiments represent a comprehensive study of SHMT1 and SHMT2 gene sequence variation and its functional implications. In addition, we obtained preliminary indications that these genes may be co-regulated with other Folate and Methionine Cycle genes.

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Section: Resultsmentioning

confidence: 99%

Serine hydroxymethyltransferase 1 and 2: gene sequence variation and functional genomic characterization

Hebbring

Chai

et al. 2012

Journal of Neurochemistry

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“…RSV Treatment Affects Steady-state AdoMet Level-Both MAT␤V1 and MAT␤V2 are known to lower the K i of MAT␣2 for AdoMet (19); and because RSV treatment decreased the association of MAT␤ with MAT␣2, we measured the steadystate AdoMet level following RSV treatment. The AdoMet level increased significantly by 20 h after RSV treatment (Fig.…”

Section: Mat2b Induction Is a Compensatory Response To Rsv Proapoptotmentioning

confidence: 99%

Methionine Adenosyltransferase 2B, HuR, and Sirtuin 1 Protein Cross-talk Impacts on the Effect of Resveratrol on Apoptosis and Growth in Liver Cancer Cells

Yang

Zheng

et al. 2013

Journal of Biological Chemistry

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Background: Methionine adenosyltransferase 2B protein (MAT␤) binds to resveratrol, but it exerts the opposite effects on growth and apoptosis. Results: Resveratrol induces HuR, SIRT1, and MAT␤ expression. These proteins interact, which stabilizes them. MAT␤ induction blunts the resveratrol effect on growth and apoptosis. Conclusion: MAT␤-HuR-SIRT1 interaction impacts resveratrol actions. Significance: This is the first demonstration of MAT␤ in SIRT1 signaling.

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“…Finally, in an attempt to begin to understand the overall regulation of the methionine and folate cycles in human liver, we performed association analyses among levels of hepatic protein for other enzymes in these pathways that had also been assayed in the same 268 liver samples used to perform the present study. Specifically, we correlated BHMT and serine hydroxymethyltransferase 1 (SHMT1) protein levels as well as the level of enzyme activity for another important methyltransferase enzyme, catechol O-methyltransferase (COMT) (Feng et al, 2009;Zhang et al, 2009;Nordgren et al, 2011) with levels of MAT1A and GNMT protein expression (Table 4). Like MAT1A and GNMT, BHMT is predominantly expressed in hepatic tissue (Li et al, 2008).…”

Section: Human Gnmt Genetic Polymorphismsmentioning

confidence: 99%

“…Tissue samples from only one sex were used to eliminate the possibility of confusion as a result of sex-dependent differences in enzyme protein expression. Characteristics of the patients from whom the biopsies were obtained have been described previously (Feng et al, 2009;Zhang et al, 2009;Nordgren et al, 2011). Use of these anonymized surgical biopsy samples was reviewed and approved by the Mayo Clinic Institutional Review Board.…”

Section: Dna Samples and Genementioning

confidence: 99%

“…1), including MAT1A and GNMT, for use in genotyping DNA samples from the same 268 human liver biopsy samples that we had phenotyped for level of hepatic MAT1A and GNMT protein. Specifically, a total of 768 tag SNPs for methionine and folate cycle genes, including 42 for MAT1A and 5 for GNMT, were selected using SNP genotype data from 168 unrelated HapMap white subjects (http://www.hapmap.org, data release 27/phase II ϩ III) as well as data from our resequencing studies for these genes (Shield et al, 2004;Martin et al, 2006;Feng et al, 2009;Nordgren et al, 2011) and SNP data obtained by using Illumina 550K and 510S genome-wide BeadChips (Illumina, Inc., San Diego, CA) and Coriell Institute-generated Affymetrix 6.0 genome-wide SNP genotypes for DNA from the 96 EA subjects included in the Coriell Institute Human Variation Panel (Camden, NJ), the same cell lines from which we obtained the DNA for our gene resequencing experiments. The SNPs were selected to tag across the genes and to include approximately 20 kb of flanking sequence, with r 2 Ն 0.8 and a minor allele frequency of Ն0.025.…”

Section: Dna Samples and Genementioning

confidence: 99%

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Human Liver Methionine Cycle:MAT1AandGNMTGene Resequencing, Functional Genomics, and Hepatic Genotype-Phenotype Correlation

et al. 2012

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ABSTRACT:The "methionine cycle" plays a critical role in the regulation of concentrations of (S)-adenosylmethionine (AdoMet), the major biological methyl donor. We set out to study sequence variation in genes encoding the enzyme that synthesizes AdoMet in liver, methionine adenosyltransferase 1A (MAT1A) and the major hepatic AdoMet using enzyme, glycine N-methyltransferase (GNMT), as well as functional implications of that variation. We resequenced MAT1A and GNMT using DNA from 288 subjects of three ethnicities, followed by functional genomic and genotype-phenotype correlation studies performed with 268 hepatic biopsy samples. We identified 44 and 42 polymorphisms in MAT1A and GNMT, respectively. Quantitative Western blot analyses for the human liver samples showed large individual variation in MAT1A and GNMT protein expression. Genotype-phenotype correlation identified two genotyped single-nucleotide polymorphisms (SNPs), reference SNP (rs) 9471976 (corrected p ‫؍‬ 3.9 ؋ 10 ؊10 ) and rs11752813 (corrected p ‫؍‬ 1.8 ؋ 10 ؊5 ), and 42 imputed SNPs surrounding GNMT that were significantly associated with hepatic GNMT protein levels (corrected p values < 0.01). Reporter gene studies showed that variant alleles for both genotyped SNPs resulted in decreased transcriptional activity. Correlation analyses among hepatic protein levels for methionine cycle enzymes showed significant correlations between GNMT and MAT1A (p ‫؍‬ 1.5 ؋ 10 ؊3) and between GNMT and betaine homocysteine methyltransferase (p ‫؍‬ 1.6 ؋ 10 ؊7 ). Our discovery of SNPs that are highly associated with hepatic GNMT protein expression as well as the "coordinate regulation" of methionine cycle enzyme protein levels provide novel insight into the regulation of this important human liver biochemical pathway.

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Methionine Adenosyltransferase 2A/2B and Methylation: Gene Sequence Variation and Functional Genomics

Cited by 22 publications

References 41 publications

Serine hydroxymethyltransferase 1 and 2: gene sequence variation and functional genomic characterization

Serine hydroxymethyltransferase 1 and 2: gene sequence variation and functional genomic characterization

Methionine Adenosyltransferase 2B, HuR, and Sirtuin 1 Protein Cross-talk Impacts on the Effect of Resveratrol on Apoptosis and Growth in Liver Cancer Cells

Human Liver Methionine Cycle:MAT1AandGNMTGene Resequencing, Functional Genomics, and Hepatic Genotype-Phenotype Correlation

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