The Catalytic Features of IDH1 Mutations Can Drive Neomorphic Activity, Phenotype Severity, and Inhibitor Binding

Abstract

Isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) balance metabolite levels by catalyzing the reversible NADP+‐dependent oxidation of isocitrate to a‐ketoglutarate (αKG). Mutations in these enzymes drive many cancers such as gliomas, leukemias, and chondrosarcomas by ablating the normal reaction and, critically, by catalyzing a neomorphic reaction: the NADPH‐dependent reduction of αKG to D‐2‐hydroxyglutarate (D2HG), an oncometabolite. Most mutations affect residue R132, and the structural and chemical diversity of the mutants observed in patients, including R132H/C/G/L/S/Q, is striking. The most common mutants in IDH1 and IDH2 serve as bona fide therapeutic targets, with selective mutant IDH inhibitors currently in the clinic. Using steady‐state kinetics methods, we recently found that the catalytic efficiency of both the normal and neomorphic reactions vary widely depending on the mutation at residue 132. Importantly, we have identified one mutant, R132Q IDH1, that preserves some wild type activity, catalyzes very highly efficient D2HG production both in biochemical and cellular models, and is resistant to allosteric mutant IDH1 inhibitors. We also show intriguing evidence that the catalytic efficiency of D2HG production appears to play a role in dictating the intensity of cellular phenotypes, allowing us to relate catalytic profiles to cancer phenotype severity. Finally, using molecular dynamics simulations and structural methods, we identified an interesting pathway of water molecules that may help drive inhibitor selectivity in mutant IDH1. By establishing the molecular mechanisms of tumor‐driving IDH mutant catalysis and inhibition, we can generate tools for predicting patient prognosis and inhibitor response, and ultimately identify new targets and handles for drug design. Support or Funding Information This work was funded by a Research Scholar Grant, RSG‐19‐075‐01‐TBE, from the American Cancer Society (C.D.S.), National Institutes of Health R00 CA187594 (C.D.S.), U54CA132384 (SDSU) & U54CA132379 (UC San Diego), MARC 5T34GM008303 (SDSU), and IMSD 5R25GM058906 (SDSU), as well as the California Metabolic Research Foundation (SDSU).