Orotate phosphoribosyltransferase (OPRT) (OPRT)

Orotate phosphoribosyltransferase (OPRT) is a fundamental enzyme in the de novo pyrimidine biosynthetic pathway, where it facilitates the conversion of orotic acid and phosphoribosyl pyrophosphate (PRPP) into orotidine 5'-monophosphate (OMP) [1][2]. In human cells, this enzymatic activity is contained within the N-terminal domain of the bifunctional protein uridine 5'-monophosphate synthase (UMPS) [2][3]. OPRT is of paramount importance in oncology as the key enzyme responsible for the initial activation of the pyrimidine analog 5-fluorouracil (5-FU) into 5-fluorouridine monophosphate (5-FUMP) [4][5]. This metabolic step is essential for the downstream production of nucleotides that inhibit thymidylate synthase and incorporate into nucleic acids, ultimately triggering apoptosis in cancer cells [5][6]. In gastrointestinal malignancies, OPRT expression is a critical determinant of therapeutic efficacy; high OPRT levels in tumor tissue are linked to improved response rates to 5-FU-based chemotherapy [7][8]. However, high OPRT activity in the normal gastrointestinal epithelium can lead to significant local toxicity, including severe diarrhea and mucositis [8]. Consequently, OPRT is a target for pharmacological modulation, such as the use of the OPRT inhibitor oteracil to reduce 5-FU-induced gastrointestinal side effects [9].

Other names

OPRTaseUridine 5'-monophosphate synthaseUMPSOrotate phosphoribosyltransferase domain

OPRT catalyzes the phosphoribosylation of 5-fluorouracil (5-FU) using phosphoribosyl pyrophosphate (PRPP) to form 5-fluorouridine monophosphate (5-FUMP), which is the rate-limiting step in the anabolic activation of 5-FU [4][5].