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O'Neill, A.G.* ; Burrell, A.L.* ; Zech, M. ; Elpeleg, O.* ; Harel, T.* ; Edvardson, S.* ; Mor-Shaked, H.* ; Rippert, A.L.* ; Nomakuchi, T.* ; Izumi, K.* ; Kollman, J.M.*

Neurodevelopmental disorder mutations in the purine biosynthetic enzyme IMPDH2 disrupt its allosteric regulation.

J. Biol. Chem. 299:105012 (2023)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Allosteric Regulation ; Cryo-electron Microscopy ; Dystonia ; Enzyme Filaments ; Enzyme Mutation ; Imp Dehydrogenase ; Neurodevelopment ; Nucleotide Biosynthesis; Inosine Monophosphate Dehydrogenase; Dominant Retinitis-pigmentosa; T-lymphocyte Activation; De-novo; Gene-expression; Cryo-em; Metabolism; System; Inhibition; Acid

ISSN (print) / ISBN 0021-9258

e-ISSN 1083-351X

Journal Journal of Biological Chemistry, The

Quellenangaben Volume: 299, Issue: 8, Article Number: 105012

Publisher American Society for Biochemistry and Molecular Biology

Publishing Place Radarweg 29, 1043 Nx Amsterdam, Netherlands

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)

Grants NEI NIH HHS
NIH HHS
NIGMS NIH HHS