Mechanism of Action of N -Acyl and N -Alkoxy Fosmidomycin Analogs: Mono- and Bisubstrate Inhibition of IspC from Plasmodium falciparum , a Causative Agent of Malaria
Abstract
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.
- Authors:
-
[1];
[2];
- Department of Chemistry and Biochemistry, George Mason University, Manassas, Virginia 20110, United States
- Progenra Inc., Malvern, Pennsylvania 19355, United States
- Department of Chemistry, The George Washington University, Washington, District of Columbia 20052, United States
- Department of Chemistry, Saint Louis University, Saint Louis, Missouri 63103, United States
- Publication Date:
- Research Org.:
- Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); US Army Medical Research and Development Command (USAMRDC); Military Infectious Disease Research Program; National Institutes of Health (NIH)
- OSTI Identifier:
- 1826235
- Alternate Identifier(s):
- OSTI ID: 1905000
- Grant/Contract Number:
- SC0014664; W81XWH-17-C-0066; W0161_15_WR; 5R01AI123433-04
- Resource Type:
- Published Article
- Journal Name:
- ACS Omega
- Additional Journal Information:
- Journal Name: ACS Omega Journal Volume: 6 Journal Issue: 42; Journal ID: ISSN 2470-1343
- Publisher:
- American Chemical Society
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; assays; inhibition; inhibitors; parasites; peptides and proteins
Citation Formats
Girma, Misgina B., Ball, Haley S., Wang, Xu, Brothers, Robert C., Jackson, Emily R., Meyers, Marvin J., Dowd, Cynthia S., and Couch, Robin D. Mechanism of Action of N -Acyl and N -Alkoxy Fosmidomycin Analogs: Mono- and Bisubstrate Inhibition of IspC from Plasmodium falciparum , a Causative Agent of Malaria. United States: N. p., 2021.
Web. doi:10.1021/acsomega.1c01711.
Girma, Misgina B., Ball, Haley S., Wang, Xu, Brothers, Robert C., Jackson, Emily R., Meyers, Marvin J., Dowd, Cynthia S., & Couch, Robin D. Mechanism of Action of N -Acyl and N -Alkoxy Fosmidomycin Analogs: Mono- and Bisubstrate Inhibition of IspC from Plasmodium falciparum , a Causative Agent of Malaria. United States. https://doi.org/10.1021/acsomega.1c01711
Girma, Misgina B., Ball, Haley S., Wang, Xu, Brothers, Robert C., Jackson, Emily R., Meyers, Marvin J., Dowd, Cynthia S., and Couch, Robin D. Fri .
"Mechanism of Action of N -Acyl and N -Alkoxy Fosmidomycin Analogs: Mono- and Bisubstrate Inhibition of IspC from Plasmodium falciparum , a Causative Agent of Malaria". United States. https://doi.org/10.1021/acsomega.1c01711.
@article{osti_1826235,
title = {Mechanism of Action of N -Acyl and N -Alkoxy Fosmidomycin Analogs: Mono- and Bisubstrate Inhibition of IspC from Plasmodium falciparum , a Causative Agent of Malaria},
author = {Girma, Misgina B. and Ball, Haley S. and Wang, Xu and Brothers, Robert C. and Jackson, Emily R. and Meyers, Marvin J. and Dowd, Cynthia S. and Couch, Robin D.},
abstractNote = {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.},
doi = {10.1021/acsomega.1c01711},
journal = {ACS Omega},
number = 42,
volume = 6,
place = {United States},
year = {Fri Oct 15 00:00:00 EDT 2021},
month = {Fri Oct 15 00:00:00 EDT 2021}
}
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