Kinetics of Plasmodium falciparum thymidylate synthase: interactions with high-affinity metabolites of 5-fluoroorotate and D1694.
Consistent with a proposed mechanism for the potent antimalarial activity of 5-fluoroorotate, 5-fluoro-2'-deoxyuridylate inhibited Plasmodium falciparum thymidylate synthase with a Ki of 2 nM. Steady-state kinetics revealed no significant differences between malarial and mammalian thymidylate synthases. Thus, additional biochemical parameters must underlie the selective antimalarial activity of 5-fluoroorotate. A polyglutamylated folate analog, D1694-(glu)4, was also a potent inhibitor of malarial thymidylate synthase (Kis = 1.5 nM).
Hekmat-Nejad
M
M
Department of Biology, Catholic University of America, Washington, D.C. 20064, USA.
Rathod
P K
PK
D000818:Animals; D000962:Antimalarials / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D005468:Fluorodeoxyuridylate / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D009963:Orotic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000201:enzymology*; D011799:Quinazolines / Q000378:metabolism* / Q000494:pharmacology*; D013876:Thiophenes / Q000378:metabolism* / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism
D000962:Antimalarials; D004791:Enzyme Inhibitors; D011799:Quinazolines; D013876:Thiophenes; D005468:Fluorodeoxyuridylate; D009963:Orotic Acid; C001242:5-fluoroorotic acid; D013940:Thymidylate Synthase; C068874:raltitrexed