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Title: Structure, Function and Inhibition of the Phosphoethanolamine Methyltransferases of the Human Malaria Parasites Plasmodium vivax and Plasmodium knowlesi

Abstract

Phosphoethanolamine methyltransferases (PMTs) catalyze the three-step methylation of phosphoethanolamine to form phosphocholine, a critical step in the synthesis of phosphatidylcholine in a select number of eukaryotes including human malaria parasites, nematodes and plants. Genetic studies in the malaria parasite Plasmodium falciparum have shown that the methyltransferase PfPMT plays a critical function in parasite development and differentiation. The presence of PMT orthologs in other malaria parasites that infect humans and their absence in mammals make them ideal targets for the development of selective antimalarials with broad specificity against different Plasmodium species. Here we describe the X-ray structures and biochemical properties of PMT orthologs from Plasmodium vivax and Plasmodium knowlesi and show that both enzymes are inhibited by amodiaquine and NSC158011, two drugs with potent antimalarial activity. Metabolic studies in a yeast mutant that relies on PkPMT or PvPMT for survival demonstrated that these compounds inhibit phosphatidylcholine biosynthesis from ethanolamine. Our structural and functional data provide insights into the mechanism of catalysis and inhibition of PMT enzymes and set the stage for a better design of more specific and selective antimalarial drugs.

Authors:
 [1];  [2];  [1];  [3];  [1];  [3];  [4];  [1]
  1. Yale Univ. School of Medicine, New Haven, CT (United States). Dept. of Internal Medicine
  2. Univ. of Illinois at Urbana-Chaimpaign, IL (United States). Dept. of Biochemistry; National Jewish Health, Denver, CO (United States). Dept. of Medicine
  3. Cornell Univ., Ithaca, NY (United States). Cornell High Energy Synchrotron Source
  4. Univ. of Illinois at Urbana-Chaimpaign, IL (United States). Dept. of Biochemistry
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH)
OSTI Identifier:
1176809
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 5; Journal Issue: 03, 2015; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Garg, Aprajita, Lukk, Tiit, Kumar, Vidya, Choi, Jae-Yeon, Augagneur, Yoann, Voelker, Dennis R., Nair, Satish, and Mamoun, Choukri Ben. Structure, Function and Inhibition of the Phosphoethanolamine Methyltransferases of the Human Malaria Parasites Plasmodium vivax and Plasmodium knowlesi. United States: N. p., 2015. Web. doi:10.1038/srep09064.
Garg, Aprajita, Lukk, Tiit, Kumar, Vidya, Choi, Jae-Yeon, Augagneur, Yoann, Voelker, Dennis R., Nair, Satish, & Mamoun, Choukri Ben. Structure, Function and Inhibition of the Phosphoethanolamine Methyltransferases of the Human Malaria Parasites Plasmodium vivax and Plasmodium knowlesi. United States. https://doi.org/10.1038/srep09064
Garg, Aprajita, Lukk, Tiit, Kumar, Vidya, Choi, Jae-Yeon, Augagneur, Yoann, Voelker, Dennis R., Nair, Satish, and Mamoun, Choukri Ben. Thu . "Structure, Function and Inhibition of the Phosphoethanolamine Methyltransferases of the Human Malaria Parasites Plasmodium vivax and Plasmodium knowlesi". United States. https://doi.org/10.1038/srep09064. https://www.osti.gov/servlets/purl/1176809.
@article{osti_1176809,
title = {Structure, Function and Inhibition of the Phosphoethanolamine Methyltransferases of the Human Malaria Parasites Plasmodium vivax and Plasmodium knowlesi},
author = {Garg, Aprajita and Lukk, Tiit and Kumar, Vidya and Choi, Jae-Yeon and Augagneur, Yoann and Voelker, Dennis R. and Nair, Satish and Mamoun, Choukri Ben},
abstractNote = {Phosphoethanolamine methyltransferases (PMTs) catalyze the three-step methylation of phosphoethanolamine to form phosphocholine, a critical step in the synthesis of phosphatidylcholine in a select number of eukaryotes including human malaria parasites, nematodes and plants. Genetic studies in the malaria parasite Plasmodium falciparum have shown that the methyltransferase PfPMT plays a critical function in parasite development and differentiation. The presence of PMT orthologs in other malaria parasites that infect humans and their absence in mammals make them ideal targets for the development of selective antimalarials with broad specificity against different Plasmodium species. Here we describe the X-ray structures and biochemical properties of PMT orthologs from Plasmodium vivax and Plasmodium knowlesi and show that both enzymes are inhibited by amodiaquine and NSC158011, two drugs with potent antimalarial activity. Metabolic studies in a yeast mutant that relies on PkPMT or PvPMT for survival demonstrated that these compounds inhibit phosphatidylcholine biosynthesis from ethanolamine. Our structural and functional data provide insights into the mechanism of catalysis and inhibition of PMT enzymes and set the stage for a better design of more specific and selective antimalarial drugs.},
doi = {10.1038/srep09064},
journal = {Scientific Reports},
number = 03, 2015,
volume = 5,
place = {United States},
year = {Thu Mar 12 00:00:00 EDT 2015},
month = {Thu Mar 12 00:00:00 EDT 2015}
}

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