{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T05:40:46Z","timestamp":1791178846336,"version":"4.1.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,3,12]],"date-time":"2015-03-12T00:00:00Z","timestamp":1426118400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,3,12]],"date-time":"2015-03-12T00:00:00Z","timestamp":1426118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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 <jats:italic>Plasmodium falciparum<\/jats:italic> 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 <jats:italic>Plasmodium<\/jats:italic> species. Here we describe the X-ray structures and biochemical properties of PMT orthologs from <jats:italic>Plasmodium vivax<\/jats:italic> and <jats:italic>Plasmodium knowlesi<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/srep09064","type":"journal-article","created":{"date-parts":[[2015,3,12]],"date-time":"2015-03-12T11:01:34Z","timestamp":1426158094000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Structure, Function and Inhibition of the Phosphoethanolamine Methyltransferases of the Human Malaria Parasites Plasmodium vivax and Plasmodium knowlesi"],"prefix":"10.1038","volume":"5","author":[{"given":"Aprajita","family":"Garg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiit","family":"Lukk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vidya","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Yeon","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoann","family":"Augagneur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis R.","family":"Voelker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish","family":"Nair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Choukri Ben","family":"Mamoun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,3,12]]},"reference":[{"key":"BFsrep09064_CR1","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1016\/S0140-6736(14)60844-8","volume":"384","author":"CJ Murray","year":"2014","unstructured":"Murray, C. J. et al. Global, regional and national incidence and mortality for HIV, tuberculosis and malaria during 1990\u20132013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384, 1005\u20131070 (2014).","journal-title":"Lancet"},{"key":"BFsrep09064_CR2","doi-asserted-by":"crossref","unstructured":"Orth, H. et al. Plasmodium knowlesi infection imported to Germany, January 2013. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 18 (2013).","DOI":"10.2807\/1560-7917.ES2013.18.44.20619"},{"key":"BFsrep09064_CR3","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1186\/1475-2875-13-168","volume":"13","author":"R Yusof","year":"2014","unstructured":"Yusof, R. et al. High proportion of knowlesi malaria in recent malaria cases in Malaysia. Malaria journal 13, 168 (2014).","journal-title":"Malaria journal"},{"key":"BFsrep09064_CR4","doi-asserted-by":"publisher","first-page":"5060","DOI":"10.1128\/AAC.02727-13","volume":"58","author":"KL Kuhen","year":"2014","unstructured":"Kuhen, K. L. et al. KAF156 Is an Antimalarial Clinical Candidate with Potential for Use in Prophylaxis, Treatment and Prevention of Disease Transmission. Antimicrob Agents Chemother 58, 5060\u20135067 (2014).","journal-title":"Antimicrob Agents Chemother"},{"key":"BFsrep09064_CR5","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1038\/nature07327","volume":"455","author":"JM Carlton","year":"2008","unstructured":"Carlton, J. M. et al. Comparative genomics of the neglected human malaria parasite Plasmodium vivax. Nature 455, 757\u2013763 (2008).","journal-title":"Nature"},{"key":"BFsrep09064_CR6","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/nature01097","volume":"419","author":"MJ Gardner","year":"2002","unstructured":"Gardner, M. J. et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419, 498\u2013511 (2002).","journal-title":"Nature"},{"key":"BFsrep09064_CR7","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1038\/nature07306","volume":"455","author":"A Pain","year":"2008","unstructured":"Pain, A. et al. The genome of the simian and human malaria parasite Plasmodium knowlesi. Nature 455, 799\u2013803 (2008).","journal-title":"Nature"},{"key":"BFsrep09064_CR8","doi-asserted-by":"crossref","unstructured":"Vial, H. J. & Ben Mamoun, C. Plasmodium lipids: Metabolism and Function. in Molecular Approaches to Malaria (ed. Sherman, I. W. ) 327\u2013352 (ASM Press, Washington D.C., 2005).","DOI":"10.1128\/9781555817558.ch17"},{"key":"BFsrep09064_CR9","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/1471-2091-11-4","volume":"11","author":"AM Bobenchik","year":"2010","unstructured":"Bobenchik, A. M. et al. Identification of inhibitors of Plasmodium falciparum phosphoethanolamine methyltransferase using an enzyme-coupled transmethylation assay. BMC Biochem 11, 4 (2010).","journal-title":"BMC Biochem"},{"key":"BFsrep09064_CR10","doi-asserted-by":"publisher","first-page":"18262","DOI":"10.1073\/pnas.1313965110","volume":"110","author":"AM Bobenchik","year":"2013","unstructured":"Bobenchik, A. M. et al. Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission. Proc Natl Acad Sci U S A 110, 18262\u201318267 (2013).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"BFsrep09064_CR11","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1021\/jm9911027","volume":"43","author":"M Calas","year":"2000","unstructured":"Calas, M. et al. Antimalarial activity of compounds interfering with Plasmodium falciparum phospholipid metabolism: comparison between mono- and bisquaternary ammonium salts. Journal of medicinal chemistry 43, 505\u2013516. (2000).","journal-title":"Journal of medicinal chemistry"},{"key":"BFsrep09064_CR12","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1074\/jbc.M111.313676","volume":"287","author":"JY Choi","year":"2012","unstructured":"Choi, J. Y., Augagneur, Y., Ben Mamoun, C. & Voelker, D. R. Identification of gene encoding Plasmodium knowlesi phosphatidylserine decarboxylase by genetic complementation in yeast and characterization of in vitro maturation of encoded enzyme. The Journal of biological chemistry 287, 222\u2013232 (2012).","journal-title":"The Journal of biological chemistry"},{"key":"BFsrep09064_CR13","doi-asserted-by":"publisher","first-page":"6206","DOI":"10.1073\/pnas.0307742101","volume":"101","author":"G Pessi","year":"2004","unstructured":"Pessi, G., Kociubinski, G. & Mamoun, C. B. A pathway for phosphatidylcholine biosynthesis in Plasmodium falciparum involving phosphoethanolamine methylation. Proc Natl Acad Sci U S A 101, 6206\u20136211 (2004).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"BFsrep09064_CR14","doi-asserted-by":"publisher","first-page":"9222","DOI":"10.1074\/jbc.M310502200","volume":"279","author":"TC Santiago","year":"2004","unstructured":"Santiago, T. C., Zufferey, R., Mehra, R. S., Coleman, R. A. & Mamoun, C. B. The Plasmodium falciparum PfGatp is an endoplasmic reticulum membrane protein important for the initial step of malarial glycerolipid synthesis. The Journal of biological chemistry 279, 9222\u20139232 (2004).","journal-title":"The Journal of biological chemistry"},{"key":"BFsrep09064_CR15","doi-asserted-by":"publisher","first-page":"27636","DOI":"10.1074\/jbc.M804360200","volume":"283","author":"WH Witola","year":"2008","unstructured":"Witola, W. H. et al. Disruption of the Plasmodium falciparum PfPMT gene results in a complete loss of phosphatidylcholine biosynthesis via the serine-decarboxylase-phosphoethanolamine-methyltransferase pathway and severe growth and survival defects. The Journal of biological chemistry 283, 27636\u201327643 (2008).","journal-title":"The Journal of biological chemistry"},{"key":"BFsrep09064_CR16","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1186\/1471-2164-9-513","volume":"9","author":"KG Le Roch","year":"2008","unstructured":"Le Roch, K. G. et al. A systematic approach to understand the mechanism of action of the bisthiazolium compound T4 on the human malaria parasite, Plasmodium falciparum. BMC Genomics 9, 513 (2008).","journal-title":"BMC Genomics"},{"key":"BFsrep09064_CR17","doi-asserted-by":"crossref","unstructured":"Vial, H. J. & Calas, M. Inhibitors of phospholipid metabolism. in Antimalarial Chemotherapy, mechanisms of action, modes of resistance and new directions in drug development (ed. Rosenthal, P. ) 347\u2013365 (Humana Press, Totowa, NJ, 2001).","DOI":"10.1385\/1-59259-111-6:347"},{"key":"BFsrep09064_CR18","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1126\/science.1067236","volume":"295","author":"K Wengelnik","year":"2002","unstructured":"Wengelnik, K. et al. A class of potent antimalarials and their specific accumulation in infected erythrocytes. Science 295, 1311\u20131314 (2002).","journal-title":"Science"},{"key":"BFsrep09064_CR19","doi-asserted-by":"publisher","first-page":"3953","DOI":"10.1016\/j.bmcl.2010.05.001","volume":"20","author":"SA Caldarelli","year":"2010","unstructured":"Caldarelli, S. A. et al. Exploration of potential prodrug approach of the bis-thiazolium salts T3 and T4 for orally delivered antimalarials. Bioorganic & medicinal chemistry letters 20, 3953\u20133956 (2010).","journal-title":"Bioorganic & medicinal chemistry letters"},{"key":"BFsrep09064_CR20","first-page":"3454","volume":"18","author":"S Peyrottes","year":"2012","unstructured":"Peyrottes, S. et al. Choline analogues in malaria chemotherapy. Current pharmaceutical design 18, 3454\u20133466 (2012).","journal-title":"Current pharmaceutical design"},{"key":"BFsrep09064_CR21","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1111\/j.1574-6976.2011.00267.x","volume":"35","author":"AM Bobenchik","year":"2011","unstructured":"Bobenchik, A. M., Augagneur, Y., Hao, B., Hoch, J. C. & Ben Mamoun, C. Phosphoethanolamine methyltransferases in phosphocholine biosynthesis: functions and potential for antiparasite therapy. FEMS Microbiol Rev 35, 609\u2013619 (2011).","journal-title":"FEMS Microbiol Rev"},{"key":"BFsrep09064_CR22","doi-asserted-by":"publisher","first-page":"173","DOI":"10.2217\/17460875.1.2.173","volume":"1","author":"G Pessi","year":"2006","unstructured":"Pessi, G. & Ben Mamoun, C. Pathways for phosphatidylcholine biosynthesis: targets and strategies for antimalarial drugs. Future Medicine, Future Lipidology 1, 173\u2013180 (2006).","journal-title":"Future Medicine, Future Lipidology"},{"key":"BFsrep09064_CR23","doi-asserted-by":"publisher","first-page":"12461","DOI":"10.1074\/jbc.M414626200","volume":"280","author":"G Pessi","year":"2005","unstructured":"Pessi, G., Choi, J. Y., Reynolds, J. M., Voelker, D. R. & Mamoun, C. B. In vivo evidence for the specificity of Plasmodium falciparum phosphoethanolamine methyltransferase and its coupling to the Kennedy pathway. The Journal of biological chemistry 280, 12461\u201312466 (2005).","journal-title":"The Journal of biological chemistry"},{"key":"BFsrep09064_CR24","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s12104-012-9372-3","volume":"7","author":"I Bezsonova","year":"2013","unstructured":"Bezsonova, I. et al. (1)H, (13)C and (15)N chemical shift assignments for PfPMT, a phosphoethanolamine methyltransferase from Plasmodium falciparum. Biomol NMR Assign 7, 17\u201320 (2013).","journal-title":"Biomol NMR Assign"},{"key":"BFsrep09064_CR25","doi-asserted-by":"publisher","first-page":"4990","DOI":"10.1016\/j.bmcl.2012.06.032","volume":"22","author":"SG Lee","year":"2012","unstructured":"Lee, S. G., Alpert, T. D. & Jez, J. M. Crystal structure of phosphoethanolamine methyltransferase from Plasmodium falciparum in complex with amodiaquine. Bioorganic & medicinal chemistry letters 22, 4990\u20134993 (2012).","journal-title":"Bioorganic & medicinal chemistry letters"},{"key":"BFsrep09064_CR26","doi-asserted-by":"publisher","first-page":"1426","DOI":"10.1074\/jbc.M111.315267","volume":"287","author":"SG Lee","year":"2012","unstructured":"Lee, S. G., Kim, Y., Alpert, T. D., Nagata, A. & Jez, J. M. Structure and reaction mechanism of phosphoethanolamine methyltransferase from the malaria parasite Plasmodium falciparum: an antiparasitic drug target. The Journal of biological chemistry 287, 1426\u20131434 (2012).","journal-title":"The Journal of biological chemistry"},{"key":"BFsrep09064_CR27","doi-asserted-by":"publisher","first-page":"33815","DOI":"10.1074\/jbc.M114.611319","volume":"289","author":"S Saen-Oon","year":"2014","unstructured":"Saen-Oon, S., Lee, S. G., Jez, J. M. & Guallar, V. An alternative mechanism for the methylation of phosphoethanolamine catalyzed by Plasmodium falciparum phosphoethanolamine methyltransferase. The Journal of biological chemistry 289, 33815\u201333825 (2014).","journal-title":"The Journal of biological chemistry"},{"key":"BFsrep09064_CR28","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1194\/jlr.M900166-JLR200","volume":"51","author":"S Dechamps","year":"2010","unstructured":"Dechamps, S. et al. Rodent and nonrodent malaria parasites differ in their phospholipid metabolic pathways. J Lipid Res 51, 81\u201396 (2010).","journal-title":"J Lipid Res"},{"key":"BFsrep09064_CR29","doi-asserted-by":"publisher","first-page":"6056","DOI":"10.1021\/bi060199d","volume":"45","author":"LH Palavalli","year":"2006","unstructured":"Palavalli, L. H. et al. Defining the role of phosphomethylethanolamine N-methyltransferase from Caenorhabditis elegans in phosphocholine biosynthesis by biochemical and kinetic analysis. Biochemistry 45, 6056\u20136065 (2006).","journal-title":"Biochemistry"},{"key":"BFsrep09064_CR30","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1042\/BJ20061815","volume":"404","author":"KM Brendza","year":"2007","unstructured":"Brendza, K. M. et al. Phosphoethanolamine N-methyltransferase (PMT-1) catalyses the first reaction of a new pathway for phosphocholine biosynthesis in Caenorhabditis elegans. The Biochemical journal 404, 439\u2013448 (2007).","journal-title":"The Biochemical journal"},{"key":"BFsrep09064_CR31","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1042\/bse0510137","volume":"51","author":"JM Sa","year":"2011","unstructured":"Sa, J. M., Chong, J. L. & Wellems, T. E. Malaria drug resistance: new observations and developments. Essays in biochemistry 51, 137\u2013160 (2011).","journal-title":"Essays in biochemistry"},{"key":"BFsrep09064_CR32","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1107\/S0907444909047374","volume":"66","author":"W Kabsch","year":"2010","unstructured":"Kabsch, W. Integration, scaling, space-group assignment and post-refinement. Acta crystallographica. Section D, Biological crystallography 66, 133\u2013144 (2010).","journal-title":"Acta crystallographica. Section D, Biological crystallography"},{"key":"BFsrep09064_CR33","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1107\/S0021889807021206","volume":"40","author":"AJ McCoy","year":"2007","unstructured":"McCoy, A. J. et al. Phaser crystallographic software. J Appl Crystallogr 40, 658\u2013674 (2007).","journal-title":"J Appl Crystallogr"},{"key":"BFsrep09064_CR34","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1107\/S0907444906022116","volume":"62","author":"K Cowtan","year":"2006","unstructured":"Cowtan, K. The Buccaneer software for automated model building. 1. Tracing protein chains. Acta crystallographica. Section D, Biological crystallography 62, 1002\u20131011 (2006).","journal-title":"Acta crystallographica. Section D, Biological crystallography"},{"key":"BFsrep09064_CR35","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1107\/S0907444909052925","volume":"66","author":"PD Adams","year":"2010","unstructured":"Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta crystallographica. Section D, Biological crystallography 66, 213\u2013221 (2010).","journal-title":"Acta crystallographica. Section D, Biological crystallography"},{"key":"BFsrep09064_CR36","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1139\/y59-099","volume":"37","author":"EG Bligh","year":"1959","unstructured":"Bligh, E. G. & Dyer, W. J. A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37, 911\u2013917 (1959).","journal-title":"Can J Biochem Physiol"},{"key":"BFsrep09064_CR37","doi-asserted-by":"publisher","first-page":"6062","DOI":"10.1074\/jbc.270.11.6062","volume":"270","author":"PJ Trotter","year":"1995","unstructured":"Trotter, P. J. & Voelker, D. R. Identification of a non-mitochondrial phosphatidylserine decarboxylase activity (PSD2) in the yeast Saccharomyces cerevisiae. The Journal of biological chemistry 270, 6062\u20136070 (1995).","journal-title":"The Journal of biological chemistry"},{"key":"BFsrep09064_CR38","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/BF02668129","volume":"1","author":"G Rouser","year":"1966","unstructured":"Rouser, G., Siakotos, A. N. & Fleischer, S. Quantitative analysis of phospholipids by thin-layer chromatography and phosphorus analysis of spots. Lipids 1, 85\u201386 (1966).","journal-title":"Lipids"},{"key":"BFsrep09064_CR39","doi-asserted-by":"crossref","first-page":"10017","DOI":"10.1016\/S0021-9258(18)82166-4","volume":"268","author":"PJ Trotter","year":"1993","unstructured":"Trotter, P. J. & Storch, J. Fatty acid esterification during differentiation of the human intestinal cell line Caco-2. The Journal of biological chemistry 268, 10017\u201310023. (1993).","journal-title":"The Journal of biological chemistry"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep09064","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep09064.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep09064.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T16:23:21Z","timestamp":1672935801000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep09064"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,3,12]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,8,14]]}},"alternative-id":["BFsrep09064"],"URL":"https:\/\/doi.org\/10.1038\/srep09064","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,3,12]]},"assertion":[{"value":"27 October 2014","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 February 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9064"}}