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Volume 26
Issue 17
10.3390/ijms26178238
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

C. elegans Cytoplasmic Isocitrate Dehydrogenase Neomorphic G98N and R133H Mutants Produce the Oncometabolite 2-Hydroxyglutarate

by
Melissa Bouchard
1,
Anne McAllister
1,
Noah S. Bourlett
1,
Chelsea Hoyt
1,
Laurent Calcul
2 and
Katherine M. Walstrom
1,*
1
Division of Natural Sciences, New College of Florida, Sarasota, FL 34243, USA
2
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(17), 8238; https://doi.org/10.3390/ijms26178238 (registering DOI)
Submission received: 4 July 2025 / Revised: 13 August 2025 / Accepted: 22 August 2025 / Published: 25 August 2025
(This article belongs to the Special Issue C. elegans as a Disease Model: Molecular Perspectives: 2nd Edition)
Versions Notes

Abstract

Isocitrate dehydrogenase (IDH) catalyzes the conversion of NAD(P)+ and isocitrate to NAD(P)H and α-ketoglutarate (αKG). The cytoplasmic enzyme IDH1 is important for producing NADPH for biosynthesis and for protecting against oxidative stress. IDH1 mutants, such as R132H found in glioblastomas and other types of human cancers, have a neomorphic activity that uses NADPH to reduce αKG to 2-hydroxyglutarate (2HG). 2HG interferes with the activity of important enzymes such as histone demethylases and TET demethylases. We hypothesized that Caenorhabditis elegans could be a good model system for studying oncogenic properties of mutant IDH1. To test this, we purified C. elegans cytoplasmic IDH-1 and two mutants, G98N and R133H, which correspond to human IDH1 mutants G97N and R132H, respectively. We found that the wild-type IDH-1 had similar kinetic properties to human IDH1, and it could produce small amounts of 2HG. We also found that the R133H mutant had a lower KM for αKG than human R132H in steady-state enzyme kinetic experiments, and it produced almost exclusively 2HG in the presence of NADPH and αKG. The G98N mutant had a higher kcat in the forward direction than the comparable human G97N mutant, and the G98N mutant produced a smaller amount of 2HG compared to the R133H mutant. These results suggest that C. elegans strains with IDH-1 mutations could be a good model system for studying the effects of 2HG in eukaryotic organisms.
Keywords: dehydrogenase; enzyme kinetics; isocitrate; 2-hydroxyglutarate; C. elegans dehydrogenase; enzyme kinetics; isocitrate; 2-hydroxyglutarate; C. elegans

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MDPI and ACS Style

Bouchard, M.; McAllister, A.; Bourlett, N.S.; Hoyt, C.; Calcul, L.; Walstrom, K.M. C. elegans Cytoplasmic Isocitrate Dehydrogenase Neomorphic G98N and R133H Mutants Produce the Oncometabolite 2-Hydroxyglutarate. Int. J. Mol. Sci. 2025, 26, 8238. https://doi.org/10.3390/ijms26178238

AMA Style

Bouchard M, McAllister A, Bourlett NS, Hoyt C, Calcul L, Walstrom KM. C. elegans Cytoplasmic Isocitrate Dehydrogenase Neomorphic G98N and R133H Mutants Produce the Oncometabolite 2-Hydroxyglutarate. International Journal of Molecular Sciences. 2025; 26(17):8238. https://doi.org/10.3390/ijms26178238

Chicago/Turabian Style

Bouchard, Melissa, Anne McAllister, Noah S. Bourlett, Chelsea Hoyt, Laurent Calcul, and Katherine M. Walstrom. 2025. "C. elegans Cytoplasmic Isocitrate Dehydrogenase Neomorphic G98N and R133H Mutants Produce the Oncometabolite 2-Hydroxyglutarate" International Journal of Molecular Sciences 26, no. 17: 8238. https://doi.org/10.3390/ijms26178238

APA Style

Bouchard, M., McAllister, A., Bourlett, N. S., Hoyt, C., Calcul, L., & Walstrom, K. M. (2025). C. elegans Cytoplasmic Isocitrate Dehydrogenase Neomorphic G98N and R133H Mutants Produce the Oncometabolite 2-Hydroxyglutarate. International Journal of Molecular Sciences, 26(17), 8238. https://doi.org/10.3390/ijms26178238

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