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

Garg, Aprajita; Lukk, Tiit; Kumar, Vidya; Choi, Jae-Yeon; Augagneur, Yoann; Voelker, Dennis R.; Nair, Satish; Mamoun, Choukri Ben

doi:10.1038/srep09064

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

Journal Article · Thu Mar 12 00:00:00 EDT 2015 · Scientific Reports

DOI:https://doi.org/10.1038/srep09064· OSTI ID:1176809

Garg, Aprajita ^[1]; Lukk, Tiit ^[2]; Kumar, Vidya ^[1]; Choi, Jae-Yeon ^[3]; Augagneur, Yoann ^[1]; Voelker, Dennis R. ^[3]; Nair, Satish ^[4]; Mamoun, Choukri Ben ^[1]

Yale Univ. School of Medicine, New Haven, CT (United States). Dept. of Internal Medicine
Univ. of Illinois at Urbana-Chaimpaign, IL (United States). Dept. of Biochemistry; National Jewish Health, Denver, CO (United States). Dept. of Medicine
Cornell Univ., Ithaca, NY (United States). Cornell High Energy Synchrotron Source
Univ. of Illinois at Urbana-Chaimpaign, IL (United States). Dept. of Biochemistry

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.

View Accepted Manuscript (DOE)

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: USDOE Office of Science (SC); NIH

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1176809

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 03, 2015 Vol. 5; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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