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TitleNeurodevelopmental disorder mutations in the purine biosynthetic enzyme IMPDH2 disrupt its allosteric regulation.
Journal, issue, pagesJ Biol Chem, Vol. 299, Issue 8, Page 105012, Year 2023
Publish dateJul 4, 2023
AuthorsAudrey 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 /
PubMed AbstractInosine 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 ...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.
External linksJ Biol Chem / PubMed:37414152 / PubMed Central
MethodsEM (single particle)
Resolution2.0 - 3.0 Å
Structure data

29357

8foz

EMDB-29357, PDB-8foz:
Human IMPDH2 mutant - L245P, treated with ATP, IMP, and NAD+; filament assembly interface reconstruction
Method: EM (single particle) / Resolution: 2.0 Å

29482

8fuz

EMDB-29482, PDB-8fuz:
Human IMPDH2 mutant - L245P, treated with GTP, ATP, IMP, and NAD+; filament assembly interface reconstruction
Method: EM (single particle) / Resolution: 2.1 Å

29848

8g8f

EMDB-29848, PDB-8g8f:
Human IMPDH2 mutant - L245P, treated with ATP, IMP, and NAD+; extended filament segment reconstruction
Method: EM (single particle) / Resolution: 2.6 Å

29863

8g9b

EMDB-29863, PDB-8g9b:
Human IMPDH2 mutant - L245P, treated with GTP, ATP, IMP, and NAD+; compressed filament segment reconstruction
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-29870: Human IMPDH2 mutant - L245P, treated with GTP, ATP, IMP, and NAD+; bent filament segment reconstruction
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-IMP:
INOSINIC ACID / Inosinic acid

ChemComp-NAD:
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD*YM / Nicotinamide adenine dinucleotide

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM / Guanosine triphosphate

Source
  • homo sapiens (human)
KeywordsOXIDOREDUCTASE / Filament / Dehydrogenase / CBS domain / Bateman domain / purine biosynthesis

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