GUK1 (guanylate kinase 1) catalyzes phosphorylation of GMP to GDP, serving as an essential enzyme in guanine nucleotide metabolism 1. The gene encodes two isoforms: a mitochondrial long form and a cytosolic short form 2. In photoreceptors, GUK1 participates in cGMP recycling and regeneration 1, while it also regulates cellular guanosine triphosphate (GTP) pools critical for MAPK signaling 3. Clinically, GUK1 deficiency causes mitochondrial DNA depletion syndrome (MDDS), characterized by ptosis, ophthalmoparesis, proximal weakness, and variable hepatopathy 2. The mitochondrial isoform maintains dNTP pools essential for mtDNA replication, while the cytosolic form affects T-lymphocyte function 2. Notably, pharmacological interventions with deoxyguanosine and forodesine can ameliorate mtDNA depletion, offering therapeutic potential 2. Beyond metabolism, GUK1 plays unexpected roles in cancer biology. In ALK-rearranged lung cancer, ALK phosphorylates GUK1 at tyrosine 74, increasing GDP biosynthesis to support oncogenic signaling 3. GUK1 is also overexpressed in GH-secreting pituitary adenomas 4 and linked to purine metabolism dysregulation in breast cancer 5. Additionally, GUK1 converts prodrugs including acyclovir and ganciclovir into active metabolites for antiviral and anticancer therapy.