KINETICS OF PLASMODIUM-FALCIPARUM THYMIDYLATE SYNTHASE - INTERACTIONSWITH HIGH-AFFINITY METABOLITES OF 5-FLUOROOROTATE AND D1694

Consistent with a proposed mechanism for the potent antimalarial activ ity of 5-fluoroorotate,5-fluors-2'deoxyuridylate inhibited Plasmodium falciparum thymidylate synthase with a K-i, of 2 nM. Steady-state kine tics revealed no significant differences between malarial and mammalia n thymidylate synthases. Thus, additional biochemical parameters must underlie the selective antimalarial activity of 5-fluorooretate. A pol yglutamylated folate analog, D1694-(glu)(4), was also a potent inhibit or of malarial thymidylate synthase (K-is = 1.5 nM).