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-fluors-2'deoxyuridylate inhibited Plasmodium falciparum thymidylate synthase with a K-i, 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-fluorooretate. A polyglutamylated folate analog, D1694-(glu)(4), was also a potent inhibitor of malarial thymidylate synthase (K-is = 1.5 nM).