biostudies-literatureDexter JPMassachusetts Institute of TechnologyPenn | Perelman School of Medicine, University of PennsylvaniaHoward Hughes Medical InstituteEIF | Stand Up To CancerHHS | NIH | National Cancer InstituteNational Science Foundation20051-20061https://www.ebi.ac.uk/biostudies/studies/S-EPMC6311528biostudies-literatureUnknown293(52)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) <i>IDH1</i> 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-The Journal of biological chemistryLack of evidence for substrate channeling or flux between wildtype and mutant isocitrate dehydrogenase to produce the oncometabolite 2-hydroxyglutarate.PMC6311528Center for Precision Medicine1462629Graduate Research Fellowship GE1144152Medical Scientist Training ProgramVander Heiden MGHosios AMDexter JPGunawardena JDasgupta TWard PSfalseLack of evidence for substrate channeling or flux between wildtype and mutant isocitrate dehydrogenase to produce the oncometabolite 2-hydroxyglutarate.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) <i>IDH1</i> 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-2018-01-01T00:00:00Z2018 Dec2026-05-04T10:22:22.974Z2025-02-19T03:39:59.687ZS-EPMC63115283038139410.1074/jbc.ra118.00427810.1074/jbc.RA118.004278