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Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates.

  • Author(s): Ye, Dan;
  • Guan, Kun-Liang;
  • Xiong, Yue
  • et al.
Abstract

Isocitrate dehydrogenases (IDH1/2) are frequently mutated in multiple types of human cancer, resulting in neomorphic enzymes that convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). The current view on the mechanism of IDH mutation holds that 2-HG acts as an antagonist of α-KG to competitively inhibit the activity of α-KG-dependent dioxygenases, including those involved in histone and DNA demethylation. Recent studies have implicated 2-HG in activities beyond epigenetic modification. Multiple enzymes have been discovered that lack mutations but that can nevertheless produce 2-HG promiscuously under hypoxic or acidic conditions. Therapies are being developed to treat IDH-mutant cancers by targeting either the mutant IDH enzymes directly or the pathways sensitized by 2-HG.

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