Roles of metal ions in the selective inhibition of oncogenic variants of isocitrate dehydrogenase 1

• DOI: 10.1038/s42003-021-02743-5
• Publication Date: 2021-11-01T11:04:13Z
• Authors: Shuang Liu; Martine I. Abboud; Tobias John; Victor Mikhailov; Ingvild Hvinden; John Walsby-Tickle; Xiao Liu; Ilaria Pettinati; Tom Cadoux-Hudson; James S. O. McCul...; Christopher J. Sc...
• Keywords: Isocitrate dehydrogenase

Abstract Cancer linked isocitrate dehydrogenase (IDH) 1 variants, notably R132H IDH1, manifest a ‘gain-of-function’ to reduce 2-oxoglutarate 2-hydroxyglutarate. High-throughput screens have enabled clinically useful IDH1 inhibitors, mostly allosteric binders at the dimer interface. We report investigations on roles of divalent metal ions in IDH substrate and inhibitor binding that rationalise this observation. Mg 2+ /Mn enhance wt but with former manifesting lower K M s. The isocitrate-Mg complex is preferred substrate; separate weaker preferred. Binding inhibitors interface weakens active site complexes; their potency affected by concentration. Inhibitor selectivity for over substantially arises from different stabilities substrate-Mg complexes. results reveal importance substrate-metal ion complexes catalysis basis selective inhibition. Further studies TCA cycle related metabolism, including an evolutionary perspective, are interest.