The complex mechanism of antimycobacterial action of 5-fluorouracil.
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Singh V, Brecik M, Mukherjee R, Evans JC, Svetlikova Z, Blasko J, Surade S, Blackburn J, Warner DF, Mikusova K, Mizrahi V
The complex mechanism of antimycobacterial action of 5-fluorouracil.
Chem Biol. 2015 Jan 22;22(1):63-75. doi: 10.1016/j.chembiol.2014.11.006. Epub 2014 Dec 24.
- PubMed ID
- 25544046 [ View in PubMed]
- Abstract
A combination of chemical genetic and biochemical assays was applied to investigate the mechanism of action of the anticancer drug 5-fluorouracil (5-FU), against Mycobacterium tuberculosis (Mtb). 5-FU resistance was associated with mutations in upp or pyrR. Upp-catalyzed conversion of 5-FU to FUMP was shown to constitute the first step in the mechanism of action, and resistance conferred by nonsynonymous SNPs in pyrR shown to be due to derepression of the pyr operon and rescue from the toxic effects of FUMP and downstream antimetabolites through de novo production of UMP. 5-FU-derived metabolites identified in Mtb were consistent with the observed incorporation of 5-FU into RNA and DNA and the reduced amount of mycolyl arabinogalactan peptidoglycan in 5-FU-treated cells. Conditional depletion of the essential thymidylate synthase ThyX resulted in modest hypersensitivity to 5-FU, implicating inhibition of ThyX by fluorodeoxyuridylate as a further component of the mechanism of antimycobacterial action of this drug.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Fluorouracil DNA Nucleotide Humans YesIncorporation into and destabilizationDetails Fluorouracil RNA Nucleotide Humans YesIncorporation into and destabilizationDetails Fluorouracil Thymidylate synthase Protein Humans YesOther/unknownDetails