Hypoxia induces production of L-2-hydroxyglutarate Journal Article

Authors: Intlekofer, A. M.; DeMatteo, R. G.; Venneti, S.; Finley, L. W. S.; Lu, C.; Judkins, A. R.; Rustenburg, A. S.; Grinaway, P. B.; Chodera, J. D.; Cross, J. R.; Thompson, C. B.
Article Title: Hypoxia induces production of L-2-hydroxyglutarate
Abstract: Somatic mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) contribute to the pathogenesis of cancer via production of the "oncometabolite" D-2-hydroxyglutarate (D-2HG). Elevated D-2HG can block differentiation of malignant cells by functioning as a competitive inhibitor of α-ketoglutarate (α-KG)-dependent enzymes, including Jumonji family histone lysine demethylases. 2HG is a chiral molecule that can exist in either the D-enantiomer or the L-enantiomer. Although cancer-associated IDH1/2 mutants produce D-2HG, biochemical studies have demonstrated that L-2HG also functions as a potent inhibitor of α-KG-dependent enzymes. Here we report that under conditions of oxygen limitation, mammalian cells selectively produce L-2HG via enzymatic reduction of α-KG. Hypoxia-induced L-2HG is not mediated by IDH1 or IDH2, but instead results from promiscuous substrate usage primarily by lactate dehydrogenase A (LDHA). During hypoxia, the resulting increase in L-2HG is necessary and sufficient for the induction of increased methylation of histone repressive marks, including histone 3 lysine 9 (H3K9me3). © 2015 Elsevier Inc.
Keywords: controlled study; human tissue; unclassified drug; human cell; mammalia; histone h3; lactate dehydrogenase; cell hypoxia; mass fragmentography; enzyme specificity; cell metabolism; glycolysis; glutamine; enzyme active site; mammal cell; 2 hydroxyglutaric acid; 2 oxoglutaric acid; isocitrate dehydrogenase 1; histone methylation; enantiomer; electron transport; redox stress; isocitrate dehydrogenase 2; hypoxic cell; human; priority journal; article; histone h3 lysine 9
Journal Title: Cell Metabolism
Volume: 22
Issue: 2
ISSN: 1550-4131
Publisher: Elsevier Inc.  
Date Published: 2015-08-04
Start Page: 304
End Page: 311
Language: English
DOI: 10.1016/j.cmet.2015.06.023
PROVIDER: scopus
PMCID: PMC4527873
PUBMED: 26212717
Notes: Export Date: 2 September 2015 -- Source: Scopus
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MSK Authors
  1. Chao Lu
    19 Lu
  2. Justin Robert Cross
    56 Cross
  3. Lydia Whitney Stillman Finley
    17 Finley
  4. Craig Bernie Thompson
    124 Thompson
  5. John Damon Chodera
    61 Chodera