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

Journal Article · · Scientific Reports
DOI:https://doi.org/10.1038/srep09064· OSTI ID:1176809
 [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
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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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC); National Institutes of Health (NIH)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1176809
Journal Information:
Scientific Reports, Vol. 5, Issue 03, 2015; ISSN 2045-2322
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 16 works
Citation information provided by
Web of Science

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Cited By (6)

Phosphoethanolamine-N-methyltransferase is a potential biomarker for the diagnosis of P. knowlesi and P. falciparum malaria journal March 2018
Seasonal Variation of Lipid Profile of Oyster Crassostrea talienwhanensis from the Yellow Sea Area journal March 2020
Computational and experimental elucidation of Plasmodium falciparum phosphoethanolamine methyltransferase inhibitors: Pivotal drug target journal August 2019
Allosteric Site Inhibitor Disrupting Auto-Processing of Malarial Cysteine Proteases journal November 2018
Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone journal June 2016
Role of phospholipid synthesis in the development and differentiation of malaria parasites in the blood journal October 2018

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