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

Audrey G O'Neill, Anika L Burrell, Michael Zech, Orly Elpeleg, Tamar Harel, Simon Edvardson, Hagar Mor-Shaked, Alyssa L Rippert, Tomoki Nomakuchi, Kosuke Izumi, Justin M Kollman

The Journal of biological chemistry 2023 Aug

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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. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Audrey G O'Neill, Anika L Burrell, Michael Zech, Orly Elpeleg, Tamar Harel, Simon Edvardson, Hagar Mor-Shaked, Alyssa L Rippert, Tomoki Nomakuchi, Kosuke Izumi, Justin M Kollman. Neurodevelopmental disorder mutations in the purine biosynthetic enzyme IMPDH2 disrupt its allosteric regulation. The Journal of biological chemistry. 2023 Aug;299(8):105012