Evaluating Mechanisms of IDH1 Regulation through Site-Specific Acetylation Mimics
| Autor: | Alexandra I Strom, Joi Weeks, Christal D. Sohl, Sati Alexander, Vinnie Widjaja, Dahra K Pucher |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
IDH1 Kinetics Mutant Lysine Proteomics Biochemistry Microbiology Article Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Humans Computer Simulation Molecular Biology acetylation Brain Neoplasms Chemistry Glioma Isocitrate Dehydrogenase Recombinant Proteins QR1-502 Glutamine 030104 developmental biology Isocitrate dehydrogenase post-translational modification Acetylation kinetics Mutation Mutagenesis Site-Directed Glioblastoma Protein Processing Post-Translational 030217 neurology & neurosurgery |
| Zdroj: | Biomolecules, Vol 11, Iss 740, p 740 (2021) Biomolecules Volume 11 Issue 5 |
| Popis: | Isocitrate dehydrogenase (IDH1) catalyzes the reversible NADP+-dependent oxidation of isocitrate to α-ketoglutarate (αKG). IDH1 mutations, primarily R132H, drive > 80% of low-grade gliomas and secondary glioblastomas and facilitate the NADPH-dependent reduction of αKG to the oncometabolite D-2-hydroxyglutarate (D2HG). While the biochemical features of human WT and mutant IDH1 catalysis have been well-established, considerably less is known about mechanisms of regulation. Proteomics studies have identified lysine acetylation in WT IDH1, indicating post-translational regulation. Here, we generated lysine to glutamine acetylation mimic mutants in IDH1 to evaluate the effects on activity. We show that mimicking lysine acetylation decreased the catalytic efficiency of WT IDH1, with less severe catalytic consequences for R132H IDH1. |
| Databáze: | OpenAIRE |
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