Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

We show that cancerassociated isocitrate dehydrogenase 1 mutations result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate

Lenny Dang; David W. White; Stefan Gross; Bryson D. Bennett; Mark A. Bittinger; Edward M. Driggers; Valeria R. Fantin; Hyun Gyung Jang; Shengfang Jin; Marie C. Keenan; Kevin M. Marks; Robert M. Prins; Patrick S. Ward; Katharine E. Yen; Linda M. Liau; Joshua D. Rabinowitz; Lewis C. Cantley; Craig B. Thompson; Matthew G. Vander Heiden; Shinsan M. Su

2009

Scholarcy highlights

  • To other genes implicated in brain tumors, the compiled evidence suggests that isocitrate dehydrogenase 1 is often the first mutation that occurs 2. While these findings suggest that IDH1 mutations are selected for early during tumorigenesis, why mutations in a single allele of IDH1 result in predilection for malignant progression is uncertain
  • To determine whether R132H mutant protein directly produced 2HG from αKG we examined the product of the mutant IDH1 reaction using negative ion mode triple quadrupole electrospray liquid chromatography-MS
  • Elevated brain levels of 2HG result in increased ROS levels, potentially contributing to an increased risk of cancer, and alterations in NADPH metabolism resulting from mutant IDH1 expression could further exacerbate this effect
  • The ability of mutant IDH1 to directly act on αKG may explain the prevalence of IDH1 mutations in tumors from CNS tissue, which are unique in their high level of glutamate uptake and its ready conversion to αKG in the cytosol, thereby providing high levels of substrate for 2HG production
  • There were no significant differences between cells expressing wild-type IDH1 when compared with parental cells
  • For crystallography studies, purified R132H IDH1 was pre-incubated with NADPH, calcium chloride, and αKG
  • Genomic sequence analysis was deployed to identify brain tumor samples containing either wild-type isocitrate dehydrogenase or mutations altering amino acid 132

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