Document Detail

Translational up-regulation of antifolate drug targets in the human malaria parasite Plasmodium falciparum upon challenge with inhibitors.
MedLine Citation:
PMID:  15138068     Owner:  NLM     Status:  MEDLINE    
The thymidylate cycle in Plasmodium falciparum is essential for cell growth and replication, and dihydrofolate reductase (DHFR), a key enzyme in this cycle, is the target of important antimalarial drugs such as pyrimethamine and cycloguanil. Following previous work, where we found no evidence of upregulation of the dhfr-ts gene upon challenge with pyrimethamine, we investigated the expression at the protein level of the bifunctional gene product, which also carries thymidylate synthase (TS) activity. Challenge of parasite cultures with fluoro-substituted bases that are specific TS inhibitors at levels close to the IC(50) resulted in five to seven-fold increases in enzyme level, as monitored by both DHFR and TS activities, while pyrimethamine and another DHFR-binding inhibitor, WR99210, induced smaller but still significant increases of approximately three-fold. However, when parasites were challenged with tetracycline, an antimalarial not directed at the folate pathway, although an increase was consistently seen above untreated controls, this was at a level of approximately 1.8-fold. These increases reflect enhanced synthesis of the DHFR-TS enzyme, rather than liberation of a latent activity, as they were completely abolished if cultures were pre-incubated with cycloheximide to block de novo protein synthesis. Moreover, none of the above antimalarial drugs was found to significantly alter absolute levels of the dhfr-ts mRNA under the conditions of challenge used. We conclude that, in common with mammalian systems, where a similar phenomenon has been reported, malaria parasites are able to significantly relieve translational constraint when faced with antifolate drug challenge. The data indicate that there is a specific component in addition to a low-level non-specific increment, and that binding to the TS domain of the DHFR-TS protein appears to be better able to relieve this constraint than binding to the DHFR domain.
Niroshini Nirmalan; Paul F G Sims; John E Hyde
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular and biochemical parasitology     Volume:  136     ISSN:  0166-6851     ISO Abbreviation:  Mol. Biochem. Parasitol.     Publication Date:  2004 Jul 
Date Detail:
Created Date:  2004-05-12     Completed Date:  2004-07-15     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8006324     Medline TA:  Mol Biochem Parasitol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  63-70     Citation Subset:  IM    
Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology (UMIST), P.O. Box 88, Manchester M60 1QD, UK.
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MeSH Terms
Enzyme Inhibitors / pharmacology
Fluorouracil / pharmacology
Folic Acid Antagonists / pharmacology*
Plasmodium falciparum / drug effects*,  enzymology
Protein Biosynthesis*
Pyrimethamine / pharmacology
Tetrahydrofolate Dehydrogenase / metabolism*
Thymidylate Synthase / antagonists & inhibitors,  metabolism*
Triazines / pharmacology
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Folic Acid Antagonists; 0/Triazines; 47326-86-3/BRL 6231; 51-21-8/Fluorouracil; 58-14-0/Pyrimethamine; EC Dehydrogenase; EC Synthase

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