ACS Omega
ACS Omega
3 years ago

Mechanism of Action of -Acyl and -Alkoxy Fosmidomycin Analogs: Mono- and Bisubstrate Inhibition of IspC from , a Causative Agent of Malaria.

Mechanism of Action of -Acyl and -Alkoxy Fosmidomycin Analogs: Mono- and Bisubstrate Inhibition of IspC from , a Causative Agent of Malaria.
Misgina B. Girma, Haley S. Ball, Xu Wang, Robert C. Brothers, Emily R. Jackson, Marvin J. Meyers, Cynthia S. Dowd, Robin D. Couch
Malaria is a global health threat that requires immediate attention. Malaria is caused by the protozoan parasite Plasmodium, the most severe form of which is Plasmodium falciparum. The methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis is essential to the survival of many human pathogens, including P. falciparum, but is absent in humans, and thus shows promise as a new antimalarial drug target. The enzyme 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) catalyzes the first committed step in the MEP pathway. In addition to a divalent cation (Mg2+), the enzyme requires the substrates 1-deoxy-D-xylulose 5-phosphate (DXP) and NADPH to catalyze its reaction. We designed N-alkoxy and N-acyl fosmidomycin analogs to inhibit the activity of P. falciparum IspC in a bisubstrate manner. Enzyme assays reveal that the N-alkoxy fosmidomycin analogs have a competitive mode of inhibition relative to both the DXP- and NADPH-binding sites, confirming a bisubstrate mode of inhibition. In contrast, the N-acyl fosmidomycin analogs demonstrate competitive inhibition with respect to DXP but uncompetitive inhibition with respect to NADPH, indicating monosubstrate inhibitory activity. Our results will have a positive impact on the discovery of novel antimalarial drugs. This article has not yet been cited by other publications.

Publisher URL: https://pubs.acs.org/doi/10.1021/acsomega.1c01711

Open URL: https://pubs.acs.org/doi/pdf/10.1021/acsomega.1c01711

DOI: 10.1021/acsomega.1c01711

Open access
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