UCK1 (uridine-cytidine kinase 1) catalyzes the phosphorylation of uridine and cytidine to their monophosphate forms (UMP and CMP) 1, functioning as a salvage pathway enzyme for pyrimidine metabolism. The enzyme accepts both ATP and GTP as phosphate donors 1 and phosphorylates multiple pyrimidine nucleoside analogs including 5-fluorouridine and 5-fluorocytidine 1. UCK1 has lower catalytic efficiency than its isoform UCK2, exhibiting 39-40 fold higher Km values for uridine and cytidine 2. UCK1 is primarily localized to the cell nucleus, distinct from the cytosolic localization of UCK2 3. When co-expressed with UCK2, UCK1 can sequester UCK2 in the nucleus, impairing UCK2 function 3. UCK1 protein stability is regulated through ubiquitination by E3 ligase KLHL2 and deubiquitination by USP28, with phosphorylation by ATM influencing this balance 4. Clinically, UCK1 is critical for activating the chemotherapeutic agent 5'-azacytidine (5'-AZA) in myelodysplastic syndromes and acute myeloid leukemia. Lower UCK1 expression correlates with poor treatment response and shorter overall survival in MDS patients 5. UCK1 downregulation represents a key mechanism of 5'-AZA resistance in AML 4. Unlike UCK2, UCK1 expression does not correlate with sensitivity to other pyrimidine analogs like RX-3117 6.