Plasmodium vivax dihydrofolate reductase as a target of sulpha drugs.
Sulpha drugs act as competitive inhibitors of p-amino benzoic acid, an intermediate in the de novo folate pathway. Dihydropteroate synthase condenses sulpha drugs into sulpha-dihydropteroate (sulpha-DHP), which competes with dihydrofolate, the dihydrofolate reductase (DHFR) substrate. This designates DHFR as a possible target of sulpha-DHP. We suggest here that Plasmodium vivax DHFR is indeed the in vivo target of sulpha drugs. The wild-type DHFR expressed in Saccharomyces cerevisiae leads to cell growth inhibition, while sensitivity to the drug is exacerbated in the mutants. Contrary to what is observed with sulphanilamide, methotrexate is less effective on P. vivax-DHFR mutants than on wild-type mutant.
Institut de Génétique et de Microbiologie, CNRS UMR 8621, Université Paris-Sud, Orsay Cedex, France.
Liselotte Yimga
LY
Djapa
Ruth
R
Zelikson
Agnes
A
Delahodde
Monique
M
Bolotin-Fukuhara
André
A
Mazabraud
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D053487:DEAD-box RNA Helicases / Q000235:genetics; D017931:DNA Primers / Q000737:chemistry; D004274:DNA, Recombinant; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D007930:Leucine / Q000494:pharmacology; D002955:Leucovorin / Q000494:pharmacology; D008727:Methotrexate / Q000494:pharmacology; D010966:Plasmodium vivax / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D000077145:Sulfanilamide; D013424:Sulfanilamides / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D014170:Transformation, Genetic
D000890:Anti-Infective Agents; D017931:DNA Primers; D004274:DNA, Recombinant; D006131:Growth Inhibitors; D029701:Saccharomyces cerevisiae Proteins; D013424:Sulfanilamides; D000077145:Sulfanilamide; D013762:Tetrahydrofolate Dehydrogenase; C414169:ECM16 protein, S cerevisiae; D053487:DEAD-box RNA Helicases; D007930:Leucine; D002955:Leucovorin; D008727:Methotrexate