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Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma.

Cell | 2018

IDH1 mutations are common in low-grade gliomas and secondary glioblastomas and cause overproduction of (R)-2HG. (R)-2HG modulates the activity of many enzymes, including some that are linked to transformation and some that are probably bystanders. Although prior work on (R)-2HG targets focused on 2OG-dependent dioxygenases, we found that (R)-2HG potently inhibits the 2OG-dependent transaminases BCAT1 and BCAT2, likely as a bystander effect, thereby decreasing glutamate levels and increasing dependence on glutaminase for the biosynthesis of glutamate and one of its products, glutathione. Inhibiting glutaminase specifically sensitized IDH mutant glioma cells to oxidative stress in vitro and to radiation in vitro and in vivo. These findings highlight the complementary roles for BCATs and glutaminase in glutamate biosynthesis, explain the sensitivity of IDH mutant cells to glutaminase inhibitors, and suggest a strategy for maximizing the effectiveness of such inhibitors against IDH mutant gliomas.

Pubmed ID: 30220459 RIS Download

Associated grants

  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM007287
  • Agency: NCI NIH HHS, United States
    Id: F30 CA183474
  • Agency: NCI NIH HHS, United States
    Id: P50 CA101942
  • Agency: NCI NIH HHS, United States
    Id: P01 CA120964
  • Agency: NCI NIH HHS, United States
    Id: R01 CA188652
  • Agency: NCI NIH HHS, United States
    Id: K99 CA188679
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM007753
  • Agency: NCI NIH HHS, United States
    Id: R35 CA210068
  • Agency: NCI NIH HHS, United States
    Id: P30 CA006516
  • Agency: NCI NIH HHS, United States
    Id: R00 CA188679
  • Agency: NCI NIH HHS, United States
    Id: P50 CA165962
  • Agency: Howard Hughes Medical Institute, United States

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