Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases

Abstract

SUMMARY IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as α-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce α-KG and accumulate an α-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.

Acute myeloid leukemia—Major progress over four decades and glimpses into the future

“…Such mutations induce neomorphic IDH enzyme activity, which leads to aberrant production of the oncometabolite 2-hydroxyglutarate (2-HG). This oncometabolite competitively inhibits alpha-ketoglutarate (aKG), and by blocking the many aKG-dependent reactions, leads to dysregulated epigenetic function, a hypermethylated phenotype, and a block in maturation leading to tumorigenesis AML [150][151][152]. Because of this knowledge, IDH inhibitors were developed.…”

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

“…Much like SDH‐ and FH‐mutated tumors, IDH‐mutated cells and tumors have been shown to exhibit a hypermethylator phenotype through the inhibition of the ten‐eleven translocation (TET) family of DNA demethylases and members of the Jumonji C‐domain histone demethylases through the competitive inhibition of αKG binding by (R)‐2HG 105, 106, 107, 108, 109. However, unlike SDH and FH mutations, the effect of (R)‐2HG on PHD activity has been the subject of some controversy.…”

Aspects moléculaires des lymphomes T périphériques (1)

“…IDH2 est muté au niveau du codon R172 chez 20 à 30 % des patients [22,25,28], et ces mutations sont souvent associées à celles de TET2 [22,23]. Les mutations d'IDH2 ont pour effet d'inhiber indirectement les oxydases dépendantes du 2-oxoglutarate et du fer, telles que les protéines de la famille TET [29]. Une mutation récurrente du gène RHOA (G17V) est observée chez environ 70 % des patients [24,25,30].…”