Lack of evidence for substrate channeling or flux between wildtype and mutant isocitrate dehydrogenase to produce the oncometabolite 2-hydroxyglutarate.

ABSTRACT: Monoallelic point mutations in the gene encoding the cytosolic, NADP⁺-dependent enzyme isocitrate dehydrogenase 1 (IDH1) cause increased production of the oncometabolite 2-hydroxyglutarate (2-HG) in multiple cancers. Most IDH1 mutant tumors retain one wildtype (WT) IDH1 allele. Several studies have proposed that retention of this WT allele is protumorigenic by facilitating substrate channeling through a WT-mutant IDH1 heterodimer, with the WT subunit generating a local supply of α-ketoglutarate and NADPH that is then consumed by the mutant subunit to produce 2-HG. Here, we confirmed that coexpression of WT and mutant IDH1 subunits leads to formation of WT-mutant hetero-oligomers and increases 2-HG production. An analysis of a recently reported crystal structure of the WT-

SUBMITTER: Dexter JP 

PROVIDER: S-EPMC6311528 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature