RRC ID 6386
Author Kim S, Park DH, Kim TH, Hwang M, Shim J.
Title Functional analysis of pyrimidine biosynthesis enzymes using the anticancer drug 5-fluorouracil in Caenorhabditis elegans.
Journal FEBS J.
Abstract Pyrimidine biosynthesis enzymes function in many cellular processes and are closely associated with pyrimidine antagonists used in cancer chemotherapy. These enzymes are well characterized from bacteria to mammals, but not in a simple metazoan. To study the pyrimidine biosynthesis pathway in Caenorhabditis elegans, we screened for mutants exhibiting resistance to the anticancer drug 5-fluorouracil (5-FU). In several strains, mutations were identified in ZK783.2, the worm homolog of human uridine phosphorylase (UP). UP is a member of the pyrimidine biosynthesis family of enzymes and is a key regulator of uridine homeostasis. C. elegans UP homologous protein (UPP-1) exhibited both uridine and thymidine phosphorylase activity in vitro. Knockdown of other pyrimidine biosynthesis enzyme homologs, such as uridine monophosphate kinase and uridine monophosphate synthetase, also resulted in 5-FU resistance. Uridine monophosphate kinase and uridine monophosphate synthetase proteins are redundant, and show different, tissue-specific expression patterns in C. elegans. Whereas pyrimidine biosynthesis pathways are highly conserved between worms and humans, no human thymidine phosphorylase homolog has been identified in C. elegans. UPP-1 functions as a key regulator of the pyrimidine salvage pathway in C. elegans, as mutation of upp-1 results in strong 5-FU resistance.
Volume 276(17)
Pages 4715-26
Published 2009-9
DOI 10.1111/j.1742-4658.2009.07168.x
PMID 19645718
MeSH Animals Antimetabolites, Antineoplastic / pharmacology* Caenorhabditis elegans / drug effects* Caenorhabditis elegans / enzymology Caenorhabditis elegans / genetics Drug Resistance Fluorouracil / pharmacology* Gene Knockdown Techniques Multienzyme Complexes / genetics Multienzyme Complexes / metabolism* Mutation Nucleoside-Phosphate Kinase / genetics Nucleoside-Phosphate Kinase / metabolism* Orotate Phosphoribosyltransferase / genetics Orotate Phosphoribosyltransferase / metabolism* Orotidine-5'-Phosphate Decarboxylase / genetics Orotidine-5'-Phosphate Decarboxylase / metabolism* Polymorphism, Single Nucleotide Pyrimidines / biosynthesis* Uridine Phosphorylase / genetics Uridine Phosphorylase / metabolism*
IF 4.739
Times Cited 12
C.elegans tm2740