Uridine 5'-monophosphate synthase (UMPS) (UMPS)

Uridine 5'-monophosphate synthase (UMPS) is a bifunctional enzyme essential for de novo pyrimidine biosynthesis, housing both orotate phosphoribosyltransferase (OPRT) and orotidine-5'-phosphate decarboxylase (ODC) activities (UniProt: P11172) [1]. In clinical oncology, the OPRT domain is the key enzyme responsible for the metabolic activation of 5-fluorouracil (5-FU) and its prodrugs into the active nucleotide 5-fluorouridine monophosphate (FUMP) (PubMed: 11507056) [2]. This activation pathway, along with related enzymes like thymidine phosphorylase and uridine phosphorylase, is critical for the drug's mechanism of action, which involves the inhibition of thymidylate synthase and the subsequent impairment of DNA synthesis and RNA processing (StatPearls: Fluorouracil) [4]. OPRT expression levels in tumor tissues serve as a significant predictive biomarker, where higher levels typically indicate a better therapeutic response to fluoropyrimidine-based regimens in gastrointestinal and colorectal cancers (PubMed: 15585602) [3]. However, the presence of OPRT in the gastrointestinal tract also mediates the activation of 5-FU in healthy tissues, leading to dose-limiting toxicities such as diarrhea and mucositis (DrugBank: DB05038) [5]. Consequently, OPRT is a dual-interest target: its systemic activity is required for efficacy, while its localized inhibition in the gut (e.g., by oteracil) is a strategy used to enhance the safety profile of 5-FU therapies (PubMed: 11507056) [2].

Other names

Orotate phosphoribosyltransferaseOPRTOPRTaseOrotidine-5'-phosphate decarboxylaseOMPdecaseUridine 5'-monophosphate synthase

The enzyme activates 5-fluorouracil by converting it to 5-fluorouridine monophosphate (FUMP), which leads to the inhibition of thymidylate synthase and disruption of RNA and DNA synthesis.