GMPR (guanosine monophosphate reductase) catalyzes the irreversible NADPH-dependent deamination of GMP to IMP, maintaining intracellular balance between adenine and guanine nucleotide pools 1. The enzyme belongs to the IMPDH/GMPR family of (β/α)8 barrel enzymes, with reaction specificity controlled by dynamic differences in cofactor and protein movements rather than active site residues alone 2. GMPR function is post-translationally regulated through phosphorylation at Tyr267 by the EPHA4 tyrosine kinase, which decreases GTP pools and suppresses RAC1 activation, thereby reducing melanoma cell invasion and tumorigenicity 3. Water molecules at the substrate/product-binding site play critical roles in catalytic activity and structural integrity, with distinct water site categories unique to normal versus cancerous protein conformations, making GMPR a target for antileukemic drug design 1. Clinically, GMPR loss-of-function variants associate with blood cell trait variations in large population studies 4. GMPR is included in multi-gene prognostic signatures for melanoma and ovarian carcinoma prognosis 5 6, suggesting its dysregulation contributes to cancer progression. Additionally, GMPR represents a potential immunological target for parasitic diseases, with computationally predicted B and T cell epitopes identified for vaccine development 7.