Altered dihydrofolate reductase in pyrimethamine-resistant Plasmodium falciparum.
Dihydrofolate reductase (EC 1.5.1.3, tetrahydrofolate dehydrogenase), the target enzyme for the chemotherapeutic attack by pyrimethamine, has been studied in drug-sensitive and resistant strains of Plasmodium falciparum. No evidence was found for overproduction of this enzyme in drug-resistant strains. Results presented here indicate that pyrimethamine resistance of P. falciparum depends on a modified dihydrofolate reductase, which shows less affinity for pyrimethamine and dihydrofolate. The inhibition constants for pyrimethamine increased from 0.19 nM for the drug-sensitive strain FCH-5 to 4.1 and 21.6 nM for the drug-resistant strains FVOR and K 1, respectively. In addition, the Km-values for dihydrofolate increased from 2.5 microM to 21 and 28 microM, respectively. The type of inhibition by pyrimethamine changed from competitive with respect to dihydrofolate in drug-sensitive strain to non-competitive in drug-resistant strains of P. falciparum.
D000818:Animals; D004351:Drug Resistance; D005492:Folic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D005493:Folic Acid Antagonists; D007700:Kinetics; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011739:Pyrimethamine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*
D005493:Folic Acid Antagonists; C010920:dihydrofolate; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine