Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

Abstract

This Article demonstrates that tumour-associated IDH1 somatic mutations result in a gain of enzyme function that causes the accumulation of R(-)-2-hydroxyglutarate (2HG). We proposed that accumulation of 2HG might drive oncogenesis, and referenced work demonstrating 2HG accumulation in patients with 2-hydroxyglutaric aciduria 1 . As a plausible mechanism of oncogenesis, we proposed that R(-)-2HG induces redox stress owing to impairment of the respiratory chain. This hypothesis suggests that R(-)-2HG may promote cancer mutations, and is consistent with the latency observed in glioma development and the fact that gliomas increase in incidence with age. Nonetheless, we do appreciate that there are other possible mechanisms by which R(-)-2HG may promote tumour formation. Further work has identified that the abnormal production of 2HG is associated with tumours bearing a mutation in either IDH1 or IDH2 and supports a link between 2HG accumulation and cancer. So far, we have not found any tumour samples containing IDH1 or IDH2 mutations that do not have increased 2HG levels. Determining the mechanistic link between 2HG accumulation and cancer formation, and how each stereoisomer of 2HG may drive malignancy by the same or distinct mechanism is the subject of continuing investigation by our group and others. Hum Genet. 2005; 76:358-360. [PubMed: 15609246] NIH Public Access

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

“…Yet, only few metabolic genes are presently known to be directly implicated in tumorigenesis. Those include mutations/loss of the genes encoding succinate dehydrogenase (SDH) complex subunits, which may cause paraganglioma (Frezza et al , 2011), the inactivation and loss of fumarate hydratase (FH), playing a casual role in hereditary leiomyomatosis and renal cell cancer (HLRCC) (Kiuru et al , 2002), and mutations in IDH1 and IDH2, which can lead to low‐grade gliomas and acute myeloid leukemia (AML) (Parsons et al , 2008; Dang et al , 2009; Mardis et al , 2009; Sciacovelli et al , 2016; Sykes et al , 2016). Overall, there is still much more to learn about the causal role of metabolic genes in cancer.…”

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

“…Mutant IDH enzymes efficiently catalyze reduction of αKG to the ‘oncometabolite’ D-2HG 3,4 . D-2HG inhibits a large family of >70 different αKG-dependent enzymes that regulate chromatin-modifications, stability of hypoxia-inducible factors, extracellular matrix maturation, and DNA repair 1 .…”

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

“…Mutations in IDH2 in gliomas occur at a much lower frequency (0–6%) than IDH1 88 in the paralogous amino acid residue—R140—but also at R172. These residues are key in the activity of IDH enzymes: Arg132 and Arg172 in IDH1 and Arg140 and Arg172 in IDH2 form hydrophilic hydrogen bonds with the α‐carboxyl and β‐carboxyl groups of isocitrate to facilitate isocitrate binding in the enzyme active site 99, 100. Mutations in these residues decrease binding affinity for isocitrate and increase binding affinity for NADPH, leading to the reduction of αKG by NADPH and the release of the (R) enantiomer of 2‐hydroxyglutarate [(R)‐2HG] 101.…”

“…Mutations in these residues decrease binding affinity for isocitrate and increase binding affinity for NADPH, leading to the reduction of αKG by NADPH and the release of the (R) enantiomer of 2‐hydroxyglutarate [(R)‐2HG] 101. The (R)‐2HG produced by the mutant IDH enzymes accumulates in cells to extremely high millimolar concentrations, disrupting a number of cellular functions 100. However, it is only the concentration and not the production of (R)‐2HG which is nonphysiological in IDH ‐mutated tumors, as it is also produced as a minor product by αKG reductase enzymes and is oxidized back to αKG by 2HG dehydrogenases 102.…”

“…Interestingly, cells expressing mutant IDH1 produce less (R)‐2HG than those with IDH2 mutations 103. Moreover, (R)‐2HG expression by mutant IDH1 is enhanced by the co‐expression of wild‐type IDH1, leading to the formation of heterodimers 100, 103. Loss of the wild‐type IDH1 expression results in a dramatic decrease in (R)‐2HG production,104 suggesting either that the presence of wild‐type IDH1 increases the enzymatic activity of mutant IDH1 toward αKG or that a cycling activity (redox neutral) permits a higher production of (R)‐2HG with a more stable cell phenotype.…”