IDH1 and central nervous system cancer: It has been suggested to be through direct use of only the (R) enantiomer by the PHDs as a substrate109, 111 or through nonenzymatic oxidation of 2HG into αKG, therefore acting as a source of the normal substrate.112 Consistent with either mechanism, IDH mutant cells display decreased HIF activation compared with their wild‐type counterparts.109 Mutations in IDH1 and IDH2, in both glioma and AML, occur early in tumor development and are thought to be mutually exclusive,52, 113 suggesting that either isoform is sufficient to confer a predisposition to or permit transformation when mutated.