Inosine monophosphate dehydrogenase 1 (IMPDH1)

IMPDH1 is a key enzyme in the purine nucleotide biosynthesis pathway, catalyzing the rate-limiting conversion of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate (XMP). This step is essential for the de novo synthesis of guanine nucleotides, crucial for DNA/RNA synthesis, signal transduction, and energy transfer. IMPDH1 typically functions as a homotetramer and contains a catalytic (β/α)8 barrel domain and a regulatory Bateman domain. It requires a monovalent cation for activation and binds IMP and NAD+ in random order. Beyond its enzymatic role, IMPDH1 exhibits moonlighting functions, including nucleic acid binding, association with polyribosomes, and potential transcriptional repression. Retina-specific splice variants exist with reduced sensitivity to GTP feedback inhibition. IMPDH1 dynamically assembles into filaments, with structures varying based on activity state and GTP binding. Mutations in the IMPDH1 gene are linked to retinitis pigmentosa type 10 (RP10). Upregulation of IMPDH1 is observed in hepatocellular carcinoma (HCC), where it supports tumor growth. IMPDH1 is a therapeutic target for antiproliferative and antiviral drugs, although challenges exist in developing specific inhibitors, particularly differentiating between mammalian and microbial isoforms.

Inhibiting the enzymatic activity of IMPDH1, which catalyzes the conversion of IMP to XMP, thereby decreasing GMP synthesis. Inhibitors may target the substrate- or cofactor-binding site.