| Literature DB >> 25544046 |
Vinayak Singh1, Miroslav Brecik2, Raju Mukherjee1, Joanna C Evans1, Zuzana Svetlíková2, Jaroslav Blaško3, Sachin Surade4, Jonathan Blackburn5, Digby F Warner1, Katarína Mikušová2, Valerie Mizrahi6.
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.Entities:
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Year: 2014 PMID： 25544046 DOI： 10.1016/j.chembiol.2014.11.006
Source DB: PubMed Journal: Chem Biol ISSN： 1074-5521