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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)
Verlagsversion DOI PMC
Free by publisher
Creative Commons Lizenzvertrag
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Journal of Biological Chemistry, The
Quellenangaben Band: 299, Heft: 8, Seiten: , Artikelnummer: 105012 Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Verlagsort Radarweg 29, 1043 Nx Amsterdam, Netherlands
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Förderungen NEI NIH HHS
NIH HHS
NIGMS NIH HHS