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Research ArticleArticle

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

Kendra K. S. Nordgren, Yi Peng, Linda L. Pelleymounter, Irene Moon, Ryan Abo, Qiping Feng, Bruce Eckloff, Vivien C. Yee, Eric Wieben and Richard M. Weinshilboum
Drug Metabolism and Disposition November 2011, 39 (11) 2135-2147; DOI: https://doi.org/10.1124/dmd.111.040857
Kendra K. S. Nordgren
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Yi Peng
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Linda L. Pelleymounter
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Irene Moon
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Ryan Abo
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Qiping Feng
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Bruce Eckloff
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Vivien C. Yee
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Eric Wieben
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Richard M. Weinshilboum
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Abstract

Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylmethionine, the major biological methyl donor. MAT1A and MAT2A encode two distinct MAT isoforms in mammals. MAT2A is expressed in nonhepatic tissues, whereas MAT1A is expressed in the liver. A third gene, MAT2B, encodes a MAT2A regulatory protein. We resequenced MAT2A and MAT2B exons, splice junctions, and flanking regions using 288 DNA samples from three ethnic groups and also imputed additional single nucleotide polymorphisms (SNPs) across both genes using data from the 1000 Genomes Project. For MAT2A, resequencing identified 74 polymorphisms, including two nonsynonymous (ns) SNPs. Functional genomic studies of wild type and the two MAT2A variant allozymes (Val11 and Val205) showed that the Val11 allozyme had approximately 40% decreases in levels of enzyme activity and immunoreactive protein after COS-1 cell transfection. For MAT2B, 44 polymorphisms, 2 nonsynonymous, were identified during resequencing. Neither of the two MAT2B nsSNPs displayed alterations in levels of protein. Imputation using 1000 Genomes Project data resulted in 1730 additional MAT2A and 1997 MAT2B polymorphisms within ± 200 kilobases of each gene, respectively. Coexpression of MAT2A and MAT2B in COS-1 cells resulted in significantly increased MAT enzyme activity that correlated with increased MAT2A and MAT2B immunoreactive protein, apparently as a result of decreased degradation. Finally, studies of mRNA expression in lymphoblastoid cells showed that 7 SNPs in MAT2A and 16 SNPs in MAT2B were significantly associated with mRNA expression with p < 0.01. These observations provide a foundation for future mechanistic and clinical translational pharmacogenomic studies of MAT2A/2B.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM28157] (to R.M.W.); the National Institutes of Health National Institute of General Medical Sciences [Grant U19-GM61388] (The Pharmacogenomics Research Network) (to R.M.W.); the National Institutes of Health National Human Genome Research Institute [Grant U01-HG05137] (to R.M.W.); the National Institutes of Health National Cancer Institute [Grant R01-CA132780] (to R.M.W.); and a PhRMA Foundation “Center of Excellence Award in Clinical Pharmacology” (to R.M.W.).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.111.040857.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    MAT
    methionine adenosyltransferase
    AdoMet
    S-adenosylmethionine
    V2
    variant 2
    kb
    kilobase
    FR
    flanking region
    ns
    nonsynonymous
    LCL
    lymphoblastoid cell lines
    PCR
    polymerase chain reaction
    ORF
    open reading frame
    COMT
    catechol O-methyltransferase
    DBA
    3,4-dihydroxybenzoic acid
    RRL
    rabbit reticulocyte lysate
    PAGE
    polyacrylamide gel electrophoresis
    DMSO
    dimethyl sulfoxide
    MG132
    carbobenzoxyl-l-leucyl-l-leucyl-l-leucinal
    3MA
    3-methyladenine
    AA
    African American
    EA
    European-American
    HCA
    Han Chinese-American
    qRT
    quantitative reverse transcription
    SNP
    single nucleotide polymorphisms
    WT
    wild type.

  • Received May 26, 2011.
  • Accepted August 3, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (11)
Drug Metabolism and Disposition
Vol. 39, Issue 11
1 Nov 2011
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Research ArticleArticle

MAT2A/2B GENE SEQUENCE VARIATION AND FUNCTIONAL GENOMICS

Kendra K. S. Nordgren, Yi Peng, Linda L. Pelleymounter, Irene Moon, Ryan Abo, Qiping Feng, Bruce Eckloff, Vivien C. Yee, Eric Wieben and Richard M. Weinshilboum
Drug Metabolism and Disposition November 1, 2011, 39 (11) 2135-2147; DOI: https://doi.org/10.1124/dmd.111.040857

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Research ArticleArticle

MAT2A/2B GENE SEQUENCE VARIATION AND FUNCTIONAL GENOMICS

Kendra K. S. Nordgren, Yi Peng, Linda L. Pelleymounter, Irene Moon, Ryan Abo, Qiping Feng, Bruce Eckloff, Vivien C. Yee, Eric Wieben and Richard M. Weinshilboum
Drug Metabolism and Disposition November 1, 2011, 39 (11) 2135-2147; DOI: https://doi.org/10.1124/dmd.111.040857
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