Structure and Function of Human Metabolic Enzyme IMP Dehydrogenase

Abstract

Many essential metabolic enzymes self-assemble into filamentous polymers which serve as a layer of allosteric regulation. One example is the highly conserved enzyme Inosine-5'-monophosphate dehydrogenase (IMPDH) that catalyzes the first committed step in GTP synthesis and dynamically forms filamentous ultrastructures in response to metabolic demands. The human IMPDH1 isoform is of particular interest because mutations in IMPDH1 lead to blindness in humans. Although IMPDH1 has two unique splice variants in the retina, very little is known about how the retinal variants are structurally or allosterically different from the canonical variant. A series of cryo-EM structures that demonstrate how the retinal splice variants control filament assembly to tune allosteric regulation. We also develop a transgenic zebrafish model to study IMPDH1-associated blindness. We anticipate these findings to be a foundation for understanding how mutations in the enzyme IMPDH1 lead to retinal degeneration in humans. Furthermore, we have shown that a well-established means of metabolic regulation - tissue-specific splice variants - can add an additional layer of allosteric regulation on top of filament assembly to finely tune complex enzyme regulation.