Uridine phosophorylase: an important enzyme in pyrimidine metabolism and fluoropyrimidine activation.
Uridine phosphorylase (UPase) is an enzyme that can convert uridine to uracil. Upon the availability of substrates, UPase can also catalyze the formation of nucleosides from uracil or 5-fluorouracil (5-FU) and ribose-1-phosphate (Rib-1-P). UPase gene expression appears featured with the developmental regulation and strictly controlled at promoter level by oncogenes, tumor suppressor genes and cytokines. UPase activity is usually elevated in various tumor tissues, and this induction appears to confer 5-FU therapeutic advantage to cancer patients. UPase is the most important phosphorylase identified up to date in the regulation of uridine homeostasis, although thymidine phosphorylase (TPase) can utilize to a certain extent uridine as a substrate. The modulation of UPase activity by its specific inhibitors such as benzylacyclouridine or the disruption of this gene greatly affects uridine metabolism and pyrimidine nucleotide biosynthesis. UPase also plays an appreciable role in the activation of 5-FU and its prodrug 5'-deoxy-5-fluorouridine (5'DFUR)/capecitabine via anabolism of 5-FU through pyrimidine salvage pathway or the phosphorolysis of 5'DFUR into 5-FU. In this review, we discuss in detail the role of UPase in the regulation of uridine homeostasis and pyrimidine metabolism and in the activation of fluoropyrimidines. To address its potential in cancer treatment, we will also discuss the regulatory mechanisms of UPase gene expression and its induction in tumor tissues.
Cao
Deliang
D
Department of Internal Medicine, Section of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. deliang.cao@yale.edu
Pizzorno
Giuseppe
G
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use; D005467:Floxuridine / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D011743:Pyrimidines / Q000096:biosynthesis / Q000378:metabolism*; D014529:Uridine / Q000378:metabolism; D014543:Uridine Phosphorylase / Q000235:genetics / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D011743:Pyrimidines; D005467:Floxuridine; D014543:Uridine Phosphorylase; D005472:Fluorouracil; C025034:doxifluridine; D014529:Uridine