ArticleThe Journal of biological chemistry2023
Neurodevelopmental disorder mutations in the purine biosynthetic enzyme IMPDH2 disrupt its allosteric regulation.
Article in The Journal of biological chemistry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 14 citations in OpenAlex.
- Divergent evolution of the PRPS enzymes across the tree of life.bioRxiv : the preprint server for biology · 2026Article
- Enzyme Assemblies in Nucleotide Metabolism: Structure, Regulation, and Disease Implications.Advances in experimental medicine and biology · 2026Review
- An IMPDH2 variant associated with neurodevelopmental disorder disrupts purine biosynthesis and somite organization.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- IMPDH and GTP Metabolism in Cancer: Mechanisms, Regulation, and Translational Scope.Cancer science · 2025Review
- Metabolic functions for molecular chaperones and stress proteins in microcephaly.Cellular and molecular life sciences : CMLS · 2025Review
- Gene Expression Analysis of HPRT-Deficient Cells Maintained with Physiological Levels of Folic Acid.Cells · 2025Article
- IMPDH2's Central Role in Cellular Growth and Diseases: A Potential Therapeutic Target.Cell proliferation · 2025Review
- Purine Metabolism and Dystonia: Perspectives of a Long-Promised Relationship.Annals of neurology · 2025Review
- Depletion of nuclear cytoophidia in Alzheimer's disease.Free neuropathology · 2025Article
- IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency.EMBO reports · 2024Article
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
Inosine 5' monophosphate dehydrogenase (IMPDH) is a critical regulatory enzyme in purine nucleotide biosynthesis that is inhibited by the downstream product GTP. Multiple point mutations in the human isoform IMPDH2 have recently been associated with dystonia and other neurodevelopmental disorders, but the effect of the mutations on enzyme function has not been described. Here, we report the identification of two additional missense variants in IMPDH2 from affected individuals and show that all of the disease-associated mutations disrupt GTP regulation. Cryo-EM structures of one IMPDH2 mutant suggest this regulatory defect arises from a shift in the conformational equilibrium toward a more active state. This structural and functional analysis provides insight into IMPDH2-associated disease mechanisms that point to potential therapeutic approaches and raises new questions about fundamental aspects of IMPDH regulation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.