IMPDH1

IMPDH1 (Inosine-5'-monophosphate dehydrogenase 1) is a rate-limiting enzyme in de novo guanine nucleotide biosynthesis that regulates purine flux and supports nucleotide homeostasis^[1][2]. It participates in metabolic adaptation through filamentous assembly in response to cellular nucleotide demand, particularly in retinal cells, where unique splice variants reduce sensitivity to GTP-mediated feedback inhibition^[3][4][5]. Mechanistically, the Bateman domain in IMPDH1 mediates ATP-dependent allosteric regulation, which distinguishes it from IMPDH2 that is AMP-regulated, resulting in isoform-specific nucleotide binding and clustering properties^[5][1]. In disease models, point mutations in IMPDH1, such as D226N and R224P, impair filament assembly or nucleotide regulation, leading to autosomal dominant retinitis pigmentosa and other retinal degenerations^[1][6][7]. These retinal variants associate with polyribosomes translating rhodopsin mRNA, suggesting a role in coordinating photoreceptor protein synthesis^[8]. Beyond ophthalmology, IMPDH1 expression is elevated in multiple tumor types and correlates with tumor progression, making it a potential therapeutic target and biomarker^[9][10][11]. Pharmacologically, inhibitors like mycophenolic acid modulate IMPDH1 activity, while emerging allosteric compounds demonstrate isoform-specific targeting and filament disruption, enabling experimental manipulation of nucleotide metabolism and translational research applications^[2]. Therefore, IMPDH1 serves as a critical metabolic regulator, disease determinant, and experimental target distinct from its paralog IMPDH2.