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Updated: Jul 5, 2025
Primary Orthotopic Glioma Xenografts Recapitulate Infiltrative Growth and Isocitrate Dehydrogenase I Mutation
Published on: January 14, 2014
Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance
Matthew Mealka1, Nicole A Sierra1, Diego Avellaneda Matteo1
1Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA.
Abstract:
Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant uniquely preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employed static and dynamic structural methods and found that, compared to R132H, the R132Q active site adopted a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling revealed a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.
Insights
Mutations in human isocitrate dehydrogenase 1 (IDH1) cause cancer by creating a new function that produces an oncometabolite. Structural studies reveal how the R132Q IDH1 mutant
Area of Science:
- Biochemistry and Cancer Biology
- Enzymology and Structural Biology
Background:
- Mutations in human isocitrate dehydrogenase 1 (IDH1) are drivers of various cancers, stemming from a neomorphic enzymatic activity that produces an oncometabolite.
- Understanding the mechanistic distinctions among IDH1 mutants is crucial for targeted cancer therapies.
Approach:
- Utilized static and dynamic structural methods to investigate the active site conformations of IDH1 mutants.
- Compared the R132Q mutant, which retains conventional activity alongside neomorphic oncometabolite production, with the R132H mutant.
Key Points:
- The R132Q IDH1 active site adopts a conformation optimized for catalysis, enhancing both conventional and neomorphic activities compared to R132H.
- Optimized substrate binding and hydride transfer mechanisms were observed in the R132Q mutant.
- Active site remodeling in R132Q suggests a mechanism for resistance to selective IDH1 inhibitors.
Conclusions:
- Elucidates the fundamental mechanisms of IDH1 activity and neomorphic function.
- Identifies specific structural features that influence IDH1 inhibitor selectivity and resistance.
- Provides insights for developing more effective and selective therapeutic strategies against IDH1-mutated cancers.
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