Structure, function and inhibition of the phosphoethanolamine methyltransferases of the human malaria parasites Plasmodium vivax and Plasmodium knowlesi

Scientific Reports
Aprajita GargChoukri Ben Mamoun

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 bet...Continue Reading

References

Oct 9, 2002·Nature·Malcolm J GardnerBart Barrell
Aug 1, 1959·Canadian Journal of Biochemistry and Physiology·E G BLIGH, W J DYER
Apr 10, 2004·Proceedings of the National Academy of Sciences of the United States of America·Gabriella PessiChoukri Ben Mamoun
Aug 25, 2006·Acta Crystallographica. Section D, Biological Crystallography·Kevin Cowtan
Oct 10, 2008·Nature·Jane M CarltonClaire M Fraser-Liggett
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Jun 30, 2009·Journal of Lipid Research·Sandrine DéchampsHenri J Vial
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Jul 8, 2010·Bioorganic & Medicinal Chemistry Letters·Sergio A CaldarelliHenri Vial
Oct 26, 2011·Essays in Biochemistry·Juliana M SáThomas E Wellems
Jul 10, 2012·Bioorganic & Medicinal Chemistry Letters·Soon Goo LeeJoseph M Jez
Oct 23, 2013·Proceedings of the National Academy of Sciences of the United States of America·April M BobenchikChoukri Ben Mamoun
Nov 2, 2013·Euro Surveillance : Bulletin Européen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin·A BartT Van Gool
Jun 3, 2014·Malaria Journal·Ruhani YusofMarlindawati Mohd Ali

❮ Previous
Next ❯

Citations

Oct 6, 2018·The Journal of Biological Chemistry·Nicole KilianChoukri Ben Mamoun
Dec 17, 2017·The Journal of Biological Chemistry·Jae-Yeon ChoiDennis R Voelker

❮ Previous
Next ❯

Methods Mentioned

BETA
NMR
methyltransferase assay
X-ray
gel filtration
scintillation

Software Mentioned

XDS
PHENIX
PHASER
BUCCANEER
COOT
Graph pad
REFINE

Related Concepts

Related Feeds

Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.