Kinetics of Plasmodium falciparum thymidylate synthase: interactions with high-affinity metabolites of 5-fluoroorotate and D1694 | Zendy

Mohammad Hekmat-Nejad | Zendy; Pradipsinh K. Rathod | Zendy

Open Access

Kinetics of Plasmodium falciparum thymidylate synthase: interactions with high-affinity metabolites of 5-fluoroorotate and D1694

Author(s) -

Mohammad Hekmat-Nejad,

Pradipsinh K. Rathod

Publication year - 1996

Publication title -

antimicrobial agents and chemotherapy

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.07

H-Index - 259

eISSN - 1070-6283

pISSN - 0066-4804

DOI - 10.1128/aac.40.7.1628

Subject(s) - thymidylate synthase , plasmodium falciparum , atp synthase , biochemistry , biology , enzyme , kinetics , enzyme kinetics , chemistry , pharmacology , fluorouracil , active site , malaria , chemotherapy , immunology , genetics , physics , quantum mechanics

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).

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