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

• Published in: Communications biology Vol. 4; no. 1; p. 1243
• Main Authors: Liu, Shuang, Abboud, Martine I., John, Tobias, Mikhailov, Victor, Hvinden, Ingvild, Walsby-Tickle, John, Liu, Xiao, Pettinati, Ilaria, Cadoux-Hudson, Tom, McCullagh, James S. O., Schofield, Christopher J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 101/6; 631/45/173; 631/67/395; 631/92/321; 631/92/56; 631/92/609; Allosteric properties; Biology; Biomedical and Life Sciences; Catalysis; Dehydrogenases; Genetic Variation; Ions; Ions - metabolism; Isocitrate dehydrogenase; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Ketoglutaric acid; Life Sciences; Magnesium; Magnesium - metabolism; Manganese - metabolism; Metal ions; Oncogenes; Tricarboxylic acid cycle
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-021-02743-5

Cancer linked isocitrate dehydrogenase (IDH) 1 variants, notably R132H IDH1, manifest a ‘gain-of-function’ to reduce 2-oxoglutarate to 2-hydroxyglutarate. High-throughput screens have enabled clinically useful R132H 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 2+ ions enhance substrate binding to wt IDH1 and R132H IDH1, but with the former manifesting lower Mg 2+ /Mn 2+ K M s. The isocitrate-Mg 2+ complex is the preferred wt IDH1 substrate; with R132H IDH1, separate and weaker binding of 2-oxoglutarate and Mg 2+ is preferred. Binding of R132H IDH1 inhibitors at the dimer interface weakens binding of active site Mg 2+ complexes; their potency is affected by the Mg 2+ concentration. Inhibitor selectivity for R132H IDH1 over wt IDH1 substantially arises from different stabilities of wt and R132H IDH1 substrate-Mg 2+ complexes. The results reveal the importance of substrate-metal ion complexes in wt and R132H IDH1 catalysis and the basis for selective R132H IDH1 inhibition. Further studies on roles of metal ion complexes in TCA cycle and related metabolism, including from an evolutionary perspective, are of interest. Liu et al investigate the effects of divalent metal ions on catalysis and inhibition of the enzyme isocitrate dehydrogenase (IDH) and its cancer-linked variant R132H. They further identify the substrates for IDH as complexes with Mg 2+ and show that allosteric inhibitors work by weakening Mg 2+ binding of R132H, providing mechanistic insights into the basis for selective R132H IDH1 inhibition.