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• W2895760106 abstract "The life cycle of malaria parasites in both their mammalian host and mosquito vector consists of multiple developmental stages that ensure proper replication and progeny survival. The transition between these stages is fueled by nutrients scavenged from the host and fed into specialized metabolic pathways of the parasite. One such pathway is used by Plasmodium falciparum, which causes the most severe form of human malaria, to synthesize its major phospholipids, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine. Much is known about the enzymes involved in the synthesis of these phospholipids, and recent advances in genetic engineering, single-cell RNA-Seq analyses, and drug screening have provided new perspectives on the importance of some of these enzymes in parasite development and sexual differentiation and have identified targets for the development of new antimalarial drugs. This Minireview focuses on two phospholipid biosynthesis enzymes of P. falciparum that catalyze phosphoethanolamine transmethylation (PfPMT) and phosphatidylserine decarboxylation (PfPSD) during the blood stages of the parasite. We also discuss our current understanding of the biochemical, structural, and biological functions of these enzymes and highlight efforts to use them as antimalarial drug targets. The life cycle of malaria parasites in both their mammalian host and mosquito vector consists of multiple developmental stages that ensure proper replication and progeny survival. The transition between these stages is fueled by nutrients scavenged from the host and fed into specialized metabolic pathways of the parasite. One such pathway is used by Plasmodium falciparum, which causes the most severe form of human malaria, to synthesize its major phospholipids, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine. Much is known about the enzymes involved in the synthesis of these phospholipids, and recent advances in genetic engineering, single-cell RNA-Seq analyses, and drug screening have provided new perspectives on the importance of some of these enzymes in parasite development and sexual differentiation and have identified targets for the development of new antimalarial drugs. This Minireview focuses on two phospholipid biosynthesis enzymes of P. falciparum that catalyze phosphoethanolamine transmethylation (PfPMT) and phosphatidylserine decarboxylation (PfPSD) during the blood stages of the parasite. We also discuss our current understanding of the biochemical, structural, and biological functions of these enzymes and highlight efforts to use them as antimalarial drug targets. Malaria is a mosquito-borne parasitic disease caused by protozoan parasites of the genus Plasmodium and is one of the leading causes of death throughout human history. The disease is endemic in 91 countries with the World Health Organization African Region carrying the biggest burden of morbidity and mortality (1World Health Organization World Malaria Report. World Health Organization, Geneva, Switzerland2017Google Scholar). Of the Plasmodium species that infect humans, Plasmodium falciparum and Plasmodium vivax account for the overall majority of malaria clinical cases, hospital stays, and death (1World Health Organization World Malaria Report. World Health Organization, Geneva, Switzerland2017Google Scholar, 2Calderaro A. Piccolo G. Gorrini C. Rossi S. Montecchini S. Dell'Anna M.L. De Conto F. Medici M.C. Chezzi C. Arcangeletti M.C. Accurate identification of the six human Plasmodium spp. causing imported malaria, including Plasmodium ovale wallikeri and Plasmodium knowlesi.Malar. J. 2013; 12 (24034175): 32110.1186/1475-2875-12-321Crossref PubMed Scopus (49) Google Scholar). In 2016, these parasites were responsible for ∼216 million clinical cases and ∼445,000 deaths (1World Health Organization World Malaria Report. World Health Organization, Geneva, Switzerland2017Google Scholar). Thanks to major international efforts aimed at implementing improved policies for control of mosquito populations, the wide use of bed nets, and the application of new therapeutic strategies, this mortality rate represents a drop of more than 50% from the ∼839,000 deaths recorded in 2000 (1World Health Organization World Malaria Report. World Health Organization, Geneva, Switzerland2017Google Scholar, 3Muema J.M. Bargul J.L. Njeru S.N. Onyango J.O. Imbahale S.S. Prospects for malaria control through manipulation of mosquito larval habitats and olfactory-mediated behavioural responses using plant-derived compounds.Parasit. Vectors. 2017; 10 (28412962): 18410.1186/s13071-017-2122-8Crossref PubMed Scopus (23) Google Scholar). However, despite this success, the death toll is still unacceptably high. Emerging drug resistance to first line therapies and the high cost of drugs continue to add more health and economic burden on the affected populations (1World Health Organization World Malaria Report. World Health Organization, Geneva, Switzerland2017Google Scholar, 4Blasco B. Leroy D. Fidock D.A. Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic.Nat. Med. 2017; 23 (28777791): 917-92810.1038/nm.4381Crossref PubMed Scopus (280) Google Scholar, 5Shretta R. Avanceña A.L. Hatefi A. The economics of malaria control and elimination: a systematic review.Malar. J. 2016; 15 (27955665): 59310.1186/s12936-016-1635-5Crossref PubMed Scopus (40) Google Scholar). The development of an effective vaccine continues to be both scientifically and technically challenging. Among multiple candidates currently in development, RTS,S/AS01 (or MosquirixTM), a recombinant protein-based vaccine that targets the major circumsporozoite protein of P. falciparum, has shown the most promise so far (6Draper S.J. Sack B.K. King C.R. Nielsen C.M. Rayner J.C. Higgins M.K. Long C.A. Seder R.A. Malaria vaccines: recent advances and new horizons.Cell Host Microbe. 2018; 24 (30001524): 43-5610.1016/j.chom.2018.06.008Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). In the absence of a vaccine with high effectiveness among the overall population, there continues to be a need for new and affordable therapies and novel therapeutic strategies to treat the disease. Plasmodium parasites have a complex life cycle in the mosquito vector and humans, involving multiple developmental stages, different morphological, biochemical, and metabolic requirements, and well-controlled and highly coordinated gene expression and regulatory mechanisms (7Ben Mamoun C. Gluzman I.Y. Hott C. MacMillan S.K. Amarakone A.S. Anderson D.L. Carlton J.M. Dame J.B. Chakrabarti D. Martin R.K. Brownstein B.H. Goldberg D.E. Co-ordinated programme of gene expression during asexual intraerythrocytic development of the human malaria parasite Plasmodium falciparum revealed by microarray analysis.Mol. Microbiol. 2001; 39 (11123685): 26-3610.1046/j.1365-2958.2001.02222.xCrossref PubMed Scopus (132) Google Scholar, 8Le Roch K.G. Zhou Y. Blair P.L. Grainger M. Moch J.K. Haynes J.D. De La Vega P. Holder A.A. Batalov S. Carucci D.J. Winzeler E.A. Discovery of gene function by expression profiling of the malaria parasite life cycle.Science. 2003; 301 (12893887): 1503-150810.1126/science.1087025Crossref PubMed Scopus (1019) Google Scholar). Following injection of the parasite into the skin of the human host by an infected female Anopheles mosquito, the parasite undergoes rapid multiplication within liver hepatocytes to produce thousands of merozoites, which are packed into host cell membrane-derived vesicles (merosomes) and safely transported past the resident macrophages (Kupffer cells) into the liver sinusoids where their invasion of the erythrocytes begins (9Phillips M.A. Burrows J.N. Manyando C. van Huijsduijnen R.H. Van Voorhis W.C. Wells T.N. Malaria.Nat. Rev. Dis. Primers. 2017; 3 (28770814)1705010.1038/nrdp.2017.50Crossref PubMed Scopus (305) Google Scholar10Santos J.M. Egarter S. Zuzarte-Luís V. Kumar H. Moreau C.A. Kehrer J. Pinto A. Costa M.D. Franke-Fayard B. Janse C.J. Frischknecht F. Mair G.R. Malaria parasite LIMP protein regulates sporozoite gliding motility and infectivity in mosquito and mammalian hosts.Elife. 2017; 6 (28525314)e2410910.7554/eLife.24109Crossref PubMed Scopus (20) Google Scholar, 11Sinnis P. Zavala F. The skin: where malaria infection and the host immune response begin.Semin. Immunopathol. 2012; 34 (23053392): 787-79210.1007/s00281-012-0345-5Crossref PubMed Scopus (52) Google Scholar12Sturm A. Amino R. van de Sand C. Regen T. Retzlaff S. Rennenberg A. Krueger A. Pollok J.M. Menard R. Heussler V.T. Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids.Science. 2006; 313 (16888102): 1287-129010.1126/science.1129720Crossref PubMed Scopus (378) Google Scholar). Within the erythrocytes, each merozoite grows to several times its original size before dividing asexually via schizogony to produce 16–32 new blood merozoites (13Cowman A.F. Crabb B.S. Invasion of red blood cells by malaria parasites.Cell. 2006; 124 (16497586): 755-76610.1016/j.cell.2006.02.006Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar, 14Grüring C. Heiber A. Kruse F. Ungefehr J. Gilberger T.W. Spielmann T. Development and host cell modifications of Plasmodium falciparum blood stages in four dimensions.Nat. Commun. 2011; 2 (21266965): 16510.1038/ncomms1169Crossref PubMed Scopus (135) Google Scholar). The intraerythrocytic life cycle ends with the rupture of the host cell. The repeated cycles of invasion and destruction of host erythrocytes are directly linked to the pathology and symptoms of the disease, which include fever, chills, and fatigue (15Srivastava A. Philip N. Hughes K.R. Georgiou K. MacRae J.I. Barrett M.P. Creek D.J. McConville M.J. Waters A.P. Stage-specific changes in Plasmodium metabolism required for differentiation and adaptation to different host and vector environments.PLoS Pathog. 2016; 12 (28027318)e100609410.1371/journal.ppat.1006094Crossref PubMed Scopus (56) Google Scholar, 16Bartoloni A. Zammarchi L. Clinical aspects of uncomplicated and severe malaria.Mediterr. J. Hematol. Infect. Dis. 2012; 4 (22708041)e2012026Crossref PubMed Google Scholar). The orchestration of the intraerythrocytic schizogony requires a complete parasitic reorganization of the metabolically reduced and terminally differentiated host erythrocyte to ensure protection against immune attacks and to facilitate nutrient supply to fuel parasite development and replication (1World Health Organization World Malaria Report. World Health Organization, Geneva, Switzerland2017Google Scholar, 17Tuteja R. Malaria-an overview.FEBS J. 2007; 274 (17824953): 4670-467910.1111/j.1742-4658.2007.05997.xCrossref PubMed Scopus (157) Google Scholar18Cyrklaff M. Sanchez C.P. Kilian N. Bisseye C. Simpore J. Frischknecht F. Lanzer M. Hemoglobins S and C interfere with actin remodeling in Plasmodium falciparum-infected erythrocytes.Science. 2011; 334 (22075726): 1283-128610.1126/science.1213775Crossref PubMed Scopus (168) Google Scholar, 19Kilian N. Srismith S. Dittmer M. Ouermi D. Bisseye C. Simpore J. Cyrklaff M. Sanchez C.P. Lanzer M. Hemoglobin S and C affect protein export in Plasmodium falciparum-infected erythrocytes.Biol. Open. 2015; 4 (25701664): 400-41010.1242/bio.201410942Crossref PubMed Scopus (29) Google Scholar20Spycher C. Rug M. Klonis N. Ferguson D.J. Cowman A.F. Beck H.P. Tilley L. Genesis of and trafficking to the Maurer's clefts of Plasmodium falciparum-infected erythrocytes.Mol. Cell. Biol. 2006; 26 (16705161): 4074-408510.1128/MCB.00095-06Crossref PubMed Scopus (102) Google Scholar). While long recognized as critical structural components for parasite development and attractive therapeutic targets, phospholipids and their by-products have also emerged (21Bobenchik A.M. Witola W.H. Augagneur Y. Nic Lochlainn L. Garg A. Pachikara N. Choi J.Y. Zhao Y.O. Usmani-Brown S. Lee A. Adjalley S.H. Samanta S. Fidock D.A. Voelker D.R. Fikrig E. Ben Mamoun C. Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission.Proc. Natl. Acad. Sci. U.S.A. 2013; 110 (24145416): 18262-1826710.1073/pnas.1313965110Crossref PubMed Scopus (52) Google Scholar) as major signaling molecules that control development and differentiation processes during Plasmodium intraerythrocytic cycle (21Bobenchik A.M. Witola W.H. Augagneur Y. Nic Lochlainn L. Garg A. Pachikara N. Choi J.Y. Zhao Y.O. Usmani-Brown S. Lee A. Adjalley S.H. Samanta S. Fidock D.A. Voelker D.R. Fikrig E. Ben Mamoun C. Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission.Proc. Natl. Acad. Sci. U.S.A. 2013; 110 (24145416): 18262-1826710.1073/pnas.1313965110Crossref PubMed Scopus (52) Google Scholar22Pessi G. Kociubinski G. Mamoun C.B. A pathway for phosphatidylcholine biosynthesis in Plasmodium falciparum involving phosphoethanolamine methylation.Proc. Natl. Acad. Sci. U.S.A. 2004; 101 (15073329): 6206-621110.1073/pnas.0307742101Crossref PubMed Scopus (133) Google Scholar, 23Witola W.H. El Bissati K. Pessi G. Xie C. Roepe P.D. Mamoun C.B. 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.J. Biol. Chem. 2008; 283 (18694927): 27636-2764310.1074/jbc.M804360200Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 24Gulati S. Ekland E.H. Ruggles K.V. Chan R.B. Jayabalasingham B. Zhou B. Mantel P.Y. Lee M.C. Spottiswoode N. Coburn-Flynn O. Hjelmqvist D. Worgall T.S. Marti M. Di Paolo G. Fidock D.A. Profiling the essential nature of lipid metabolism in asexual blood and gametocyte stages of Plasmodium falciparum.Cell Host Microbe. 2015; 18 (26355219): 371-38110.1016/j.chom.2015.08.003Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 25Flammersfeld A. Lang C. Flieger A. Pradel G. Phospholipases during membrane dynamics in malaria parasites.Int. J. Med. Microbiol. 2017; 2017 (S1438-4221(17)30284-9) (28988696)10.1016/j.ijmm.2017.09.015Google Scholar26Ramakrishnan S. Serricchio M. Striepen B. Butikofer P. Lipid synthesis in protozoan parasites: a comparison between kinetoplastids and apicomplexans.Prog. Lipid Res. 2013; 52 (23827884): 488-51210.1016/j.plipres.2013.06.003Crossref PubMed Scopus (104) Google Scholar). The rapid generation of abundant parasitic progeny requires the appropriate amount of suitable lipid species at the proper compartment and at the right time to establish an active membrane biogenesis, which leads to a dramatically elevated lipid metabolism during the intraerythrocytic schizogony (22Pessi G. Kociubinski G. Mamoun C.B. A pathway for phosphatidylcholine biosynthesis in Plasmodium falciparum involving phosphoethanolamine methylation.Proc. Natl. Acad. Sci. U.S.A. 2004; 101 (15073329): 6206-621110.1073/pnas.0307742101Crossref PubMed Scopus (133) Google Scholar, 27Mitamura T. Palacpac N.M. Lipid metabolism in Plasmodium falciparum-infected erythrocytes: possible new targets for malaria chemotherapy.Microbes Infect. 2003; 5 (12758284): 545-55210.1016/S1286-4579(03)00070-4Crossref PubMed Scopus (43) Google Scholar). To acquire the necessary lipid species for different compartments, the parasite either synthesizes them de novo from previously produced metabolites or uses exogenous sources such as the erythrocyte membrane or the human plasma. This results in a 6-fold increase in the relative levels of phospholipids in the infected erythrocyte (24Gulati S. Ekland E.H. Ruggles K.V. Chan R.B. Jayabalasingham B. Zhou B. Mantel P.Y. Lee M.C. Spottiswoode N. Coburn-Flynn O. Hjelmqvist D. Worgall T.S. Marti M. Di Paolo G. Fidock D.A. Profiling the essential nature of lipid metabolism in asexual blood and gametocyte stages of Plasmodium falciparum.Cell Host Microbe. 2015; 18 (26355219): 371-38110.1016/j.chom.2015.08.003Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 27Mitamura T. Palacpac N.M. Lipid metabolism in Plasmodium falciparum-infected erythrocytes: possible new targets for malaria chemotherapy.Microbes Infect. 2003; 5 (12758284): 545-55210.1016/S1286-4579(03)00070-4Crossref PubMed Scopus (43) Google Scholar, 28Pessi G. Mamoun C.B. Pathways for phosphatidylcholine biosynthesis: targets and strategies for antimalarial drugs.Future Lipidol. 2006; 1: 173-180Crossref Google Scholar). The dependence on phospholipids for rapid parasite multiplication and the uniqueness of some of the steps in the pathways of Plasmodium lipid metabolism create significant opportunities for the identification of antimalarial drug targets (22Pessi G. Kociubinski G. Mamoun C.B. A pathway for phosphatidylcholine biosynthesis in Plasmodium falciparum involving phosphoethanolamine methylation.Proc. Natl. Acad. Sci. U.S.A. 2004; 101 (15073329): 6206-621110.1073/pnas.0307742101Crossref PubMed Scopus (133) Google Scholar, 24Gulati S. Ekland E.H. Ruggles K.V. Chan R.B. Jayabalasingham B. Zhou B. Mantel P.Y. Lee M.C. Spottiswoode N. Coburn-Flynn O. Hjelmqvist D. Worgall T.S. Marti M. Di Paolo G. Fidock D.A. Profiling the essential nature of lipid metabolism in asexual blood and gametocyte stages of Plasmodium falciparum.Cell Host Microbe. 2015; 18 (26355219): 371-38110.1016/j.chom.2015.08.003Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 27Mitamura T. Palacpac N.M. Lipid metabolism in Plasmodium falciparum-infected erythrocytes: possible new targets for malaria chemotherapy.Microbes Infect. 2003; 5 (12758284): 545-55210.1016/S1286-4579(03)00070-4Crossref PubMed Scopus (43) Google Scholar). Asexual blood stages and gametocytes of Plasmodium parasites are able to scavenge or synthesize up to 300 different lipid species to facilitate growth, proliferation, transmission, and sexual reproduction (24Gulati S. Ekland E.H. Ruggles K.V. Chan R.B. Jayabalasingham B. Zhou B. Mantel P.Y. Lee M.C. Spottiswoode N. Coburn-Flynn O. Hjelmqvist D. Worgall T.S. Marti M. Di Paolo G. Fidock D.A. Profiling the essential nature of lipid metabolism in asexual blood and gametocyte stages of Plasmodium falciparum.Cell Host Microbe. 2015; 18 (26355219): 371-38110.1016/j.chom.2015.08.003Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). The phospholipid classes, phosphatidylcholine (PC), 3The abbreviations used are: PCphosphatidylcholinePEphosphatidylethanolamineCDPcytidine diphosphateDAGdiacylglycerollyso-PClysophosphatidylcholinePSDPS decarboxylasePfNSMlyso-PC–dependent phospholipase C (SM/LCPL-phospholipase C or PLC)PfPSDP. falciparum phosphatidylserine decarboxylasePfPSSP. falciparum phosphatidylserine synthasePfPMTP. falciparum phosphoethanolamine methyltransferasePSphosphatidylserinePvPMTP. vivax phosphoethanolamine methyltransferasePMTphosphoethanolamine methyltransferaseTMtransmembrane domain7CPQA7-chloro-N-(4-ethoxyphenyl)-4-quinolinamine. phosphatidylethanolamine (PE), and phosphatidylserine (PS), are the major lipid components that define Plasmodium membranes (21Bobenchik A.M. Witola W.H. Augagneur Y. Nic Lochlainn L. Garg A. Pachikara N. Choi J.Y. Zhao Y.O. Usmani-Brown S. Lee A. Adjalley S.H. Samanta S. Fidock D.A. Voelker D.R. Fikrig E. Ben Mamoun C. Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission.Proc. Natl. Acad. Sci. U.S.A. 2013; 110 (24145416): 18262-1826710.1073/pnas.1313965110Crossref PubMed Scopus (52) Google Scholar, 22Pessi G. Kociubinski G. Mamoun C.B. A pathway for phosphatidylcholine biosynthesis in Plasmodium falciparum involving phosphoethanolamine methylation.Proc. Natl. Acad. Sci. U.S.A. 2004; 101 (15073329): 6206-621110.1073/pnas.0307742101Crossref PubMed Scopus (133) Google Scholar23Witola W.H. El Bissati K. Pessi G. Xie C. Roepe P.D. Mamoun C.B. 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.J. Biol. Chem. 2008; 283 (18694927): 27636-2764310.1074/jbc.M804360200Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 25Flammersfeld A. Lang C. Flieger A. Pradel G. Phospholipases during membrane dynamics in malaria parasites.Int. J. Med. Microbiol. 2017; 2017 (S1438-4221(17)30284-9) (28988696)10.1016/j.ijmm.2017.09.015Google Scholar, 29Choi J.Y. Kumar V. Pachikara N. Garg A. Lawres L. Toh J.Y. Voelker D.R. Ben Mamoun C. Characterization of Plasmodium phosphatidylserine decarboxylase expressed in yeast and application for inhibitor screening.Mol. Microbiol. 2016; 99 (26585333): 999-101410.1111/mmi.13280Crossref PubMed Scopus (20) Google Scholar30Ben Mamoun C. Prigge S.T. Vial H. Targeting the lipid metabolic pathways for the treatment of malaria.Drug Dev. Res. 2010; 71 (20559451): 44-55PubMed Google Scholar, 31Elabbadi N. Ancelin M.L. Vial H.J. Phospholipid metabolism of serine in Plasmodium-infected erythrocytes involves phosphatidylserine and direct serine decarboxylation.Biochem. J. 1997; 324 (9182701): 435-44510.1042/bj3240435Crossref PubMed Scopus (60) Google Scholar32Eda S. Sherman I.W. Cytoadherence of malaria-infected red blood cells involves exposure of phosphatidylserine.Cell. Physiol. Biochem. 2002; 12 (12438774): 373-38410.1159/000067908Crossref PubMed Scopus (128) Google Scholar). In the uninfected erythrocytes, PC, PE, and PS constitute 30–40, 25–35, and 10–20% of the total phospholipids, respectively, whereas in P. falciparum-infected erythrocytes and in purified parasites, these major phospholipids constitute 20–55, 15–40, and 4–15% of the total phospholipids, respectively (Table 1) (25Flammersfeld A. Lang C. Flieger A. Pradel G. Phospholipases during membrane dynamics in malaria parasites.Int. J. Med. Microbiol. 2017; 2017 (S1438-4221(17)30284-9) (28988696)10.1016/j.ijmm.2017.09.015Google Scholar, 33Wein S. Ghezal S. Buré C. Maynadier M. Périgaud C. Vial H.J. Lefebvre-Tournier I. Wengelnik K. Cerdan R. Contribution of the precursors and interplay of the pathways in the phospholipid metabolism of the malaria parasite.J. Lipid Res. 2018; 59 (29853527): 1461-147110.1194/jlr.M085589Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). The reported higher levels of PE in P. falciparum membranes compared with the membranes of other eukaryotes (Table 1) have been proposed to be largely due to the inability of the parasite to directly convert PE to PC (22Pessi G. Kociubinski G. Mamoun C.B. A pathway for phosphatidylcholine biosynthesis in Plasmodium falciparum involving phosphoethanolamine methylation.Proc. Natl. Acad. Sci. U.S.A. 2004; 101 (15073329): 6206-621110.1073/pnas.0307742101Crossref PubMed Scopus (133) Google Scholar, 23Witola W.H. El Bissati K. Pessi G. Xie C. Roepe P.D. Mamoun C.B. 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.J. Biol. Chem. 2008; 283 (18694927): 27636-2764310.1074/jbc.M804360200Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). However, P. falciparum is able to generate phosphocholine, a precursor for the synthesis of PC, from phosphoethanolamine via the PMT pathway (see below). With the exception of a few pathways, which have been identified through metabolic and genetic analyses, most components of the PC, PE, and PS biosynthetic machineries have been identified by searching for homologs in the Plasmodium genome databases of well-characterized enzymes from yeast, plants, and other eukaryotes (22Pessi G. Kociubinski G. Mamoun C.B. A pathway for phosphatidylcholine biosynthesis in Plasmodium falciparum involving phosphoethanolamine methylation.Proc. Natl. Acad. Sci. U.S.A. 2004; 101 (15073329): 6206-621110.1073/pnas.0307742101Crossref PubMed Scopus (133) Google Scholar, 30Ben Mamoun C. Prigge S.T. Vial H. Targeting the lipid metabolic pathways for the treatment of malaria.Drug Dev. Res. 2010; 71 (20559451): 44-55PubMed Google Scholar). These pathways are outlined in Fig. 1.Table 1Phospholipid composition of different eukaryotic cellsOrganism/cellPCPEPSRefs.Uninfected erythrocytes30–40%25–35%10–20%33Wein S. Ghezal S. Buré C. Maynadier M. Périgaud C. Vial H.J. Lefebvre-Tournier I. Wengelnik K. Cerdan R. Contribution of the precursors and interplay of the pathways in the phospholipid metabolism of the malaria parasite.J. Lipid Res. 2018; 59 (29853527): 1461-147110.1194/jlr.M085589Abstract Full Text Full Text PDF PubMed Scopus (24) Google ScholarP. falciparum-infected erythrocytes and free parasites20–55%15–40%4–15%25Flammersfeld A. Lang C. Flieger A. Pradel G. Phospholipases during membrane dynamics in malaria parasites.Int. J. Med. Microbiol. 2017; 2017 (S1438-4221(17)30284-9) (28988696)10.1016/j.ijmm.2017.09.015Google Scholar, 33Wein S. Ghezal S. Buré C. Maynadier M. Périgaud C. Vial H.J. Lefebvre-Tournier I. Wengelnik K. Cerdan R. Contribution of the precursors and interplay of the pathways in the phospholipid metabolism of the malaria parasite.J. Lipid Res. 2018; 59 (29853527): 1461-147110.1194/jlr.M085589Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 37Vial H.J. Ancelin M.L. Malarial lipids. An overview.Subcell Biochem. 1992; 18 (1485354): 259-30610.1007/978-1-4899-1651-8_8Crossref PubMed Scopus (94) Google ScholarTrypanosoma brucei45–60%10–20%<4%36Smith T.K. Bütikofer P. Lipid metabolism in Trypanosoma brucei.Mol. Biochem. Parasitol. 2010; 172 (20382188): 66-7910.1016/j.molbiopara.2010.04.001Crossref PubMed Scopus (78) Google ScholarToxoplasma gondii (free parasites)75%10%6%34Gupta N. Zahn M.M. Coppens I. Joiner K.A. Voelker D.R. Selective disruption of phosphatidylcholine metabolism of the intracellular parasite Toxoplasma gondii arrests its growth.J. Biol. Chem. 2005; 280 (15708856): 16345-1635310.1074/jbc.M501523200Abstract Full Text Full Text PDF PubMed Scopus (68) Google ScholarAspergillus niger51%28.5%5%35Gealt M.A. Abdollahi A. Evans J.L. Lipids and lipoidal mycotoxins of fungi.Curr. Top. Med. Mycol. 1989; 3 (2688917): 218-24710.1007/978-1-4612-3624-5_9Crossref PubMed Scopus (2) Google ScholarCandida albicans40%25.3%12%35Gealt M.A. Abdollahi A. Evans J.L. Lipids and lipoidal mycotoxins of fungi.Curr. Top. Med. Mycol. 1989; 3 (2688917): 218-24710.1007/978-1-4612-3624-5_9Crossref PubMed Scopus (2) Google ScholarCryptococcus neoformans49%28%8%35Gealt M.A. Abdollahi A. Evans J.L. Lipids and lipoidal mycotoxins of fungi.Curr. Top. Med. Mycol. 1989; 3 (2688917): 218-24710.1007/978-1-4612-3624-5_9Crossref PubMed Scopus (2) Google ScholarMicrosporum gypseum23.1%29.8%19.4%35Gealt M.A. Abdollahi A. Evans J.L. Lipids and lipoidal mycotoxins of fungi.Curr. Top. Med. Mycol. 1989; 3 (2688917): 218-24710.1007/978-1-4612-3624-5_9Crossref PubMed Scopus (2) Google Scholar Open table in a new tab phosphatidylcholine phosphatidylethanolamine cytidine diphosphate diacylglycerol lysophosphatidylcholine PS decarboxylase lyso-PC–dependent phospholipase C (SM/LCPL-phospholipase C or PLC) P. falciparum phosphatidylserine decarboxylase P. falciparum phosphatidylserine synthase P. falciparum phosphoethanolamine methyltransferase phosphatidylserine P. vivax phosphoethanolamine methyltransferase phosphoethanolamine methyltransferase transmembrane domain 7-chloro-N-(4-ethoxyphenyl)-4-quinolinamine. In most eukaryotic membranes (see Table 1), PC accounts for more than 50% of phospholipids and spontaneously self-organizes to a planar bilayer (38van Meer G. Voelker D.R. Feigenson G.W. Membrane lipids: where they are and how they behave.Nat. Rev. Mol. Cell Biol. 2008; 9 (18216768): 112-12410.1038/nrm2330Crossref PubMed Scopus (4483) Google Scholar, 39Schuler M.H. Di Bartolomeo F. Böttinger L. Horvath S.E. Wenz L.S. Daum G. Becker T. Phosphatidylcholine affects the role of the sorting and assembly machinery in the biogenesis of mitochondrial β-barrel proteins.J. Biol. Chem. 2015; 290 (26385920): 26523-2653210.1074/jbc.M115.687921Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). In addition to its structural role, PC can also modulate cellular signaling functions because its hydrolysis by phospholipases leads to the formation of the second messenger diacylglycerol (DAG), which is critical for activation of specific classes of protein kinases (40Mohammadi A.S. Li X. Ewing A.G. Mass spectrometry imaging suggests that cisplatin affects exocytotic release by alteration of cell membrane lipids.Anal. Chem. 2018; 90 (29912552): 8509-851610.1021/acs.analchem.8b01395Crossref PubMed Scopus (24) Google Scholar, 41Cooke M. Magimaidas A. Casado-Medrano V. Kazanietz M.G. Protein kinase C in cancer: the top five unanswered questions.Mol. Carcinog. 2017; 56 (28112438): 1531-154210.1002/mc.22617Crossref PubMed Scopus (47) Google Scholar). Changes in cellular PC levels have been shown to alter cell proliferation, differentiation, as well as membrane movement (42Farine L. Niemann M. Schneider A. Bütikofer P. Phosphatidylethanolamine and phosphatidylcholine biosynthesis by the Kennedy pathway occurs at different sites in Trypanosoma brucei.Sci. Rep. 2015; 5 (26577437)1678710.1038/srep16787Crossref PubMed Scopus (44) Google Scholar). Studies in malaria parasites have shown that PC is the major phospholipid in Plasmodium membranes during both liver stage and intraerythrocytic schizogony (22Pessi G. Kociubinski G. Mamoun C.B. A pathway for phosphatidylcholine biosynthesis in Plasmodium falciparum involving phosphoethanolamine methylation.Proc. Natl. Acad. Sci. U.S.A. 2004; 101 (15073329): 6206-621110.1073/pnas.0307742101Crossref PubMed Scopus (133) Google Scholar, 30Ben Mamoun C. Prigge S.T. Vial H. Targeting the lipid me" @default.
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• W2895760106 title "Role of phospholipid synthesis in the development and differentiation of malaria parasites in the blood" @default.
• W2895760106 cites W1481171708 @default.
• W2895760106 cites W1549763585 @default.
• W2895760106 cites W1579180733 @default.
• W2895760106 cites W1588347494 @default.
• W2895760106 cites W1820161030 @default.
• W2895760106 cites W1848942581 @default.
• W2895760106 cites W1964862441 @default.
• W2895760106 cites W1968876624 @default.
• W2895760106 cites W1970438062 @default.
• W2895760106 cites W1971288128 @default.
• W2895760106 cites W1971772314 @default.
• W2895760106 cites W1972810184 @default.
• W2895760106 cites W1974858723 @default.
• W2895760106 cites W1976004857 @default.
• W2895760106 cites W1981635932 @default.
• W2895760106 cites W1981723999 @default.
• W2895760106 cites W1982630721 @default.
• W2895760106 cites W1986648162 @default.
• W2895760106 cites W1990402424 @default.
• W2895760106 cites W1991105254 @default.
• W2895760106 cites W1998147246 @default.
• W2895760106 cites W1999947599 @default.
• W2895760106 cites W2002887973 @default.
• W2895760106 cites W2020796977 @default.
• W2895760106 cites W2022177860 @default.
• W2895760106 cites W2025751369 @default.
• W2895760106 cites W2026483075 @default.
• W2895760106 cites W2028978429 @default.
• W2895760106 cites W2029053329 @default.
• W2895760106 cites W2031502544 @default.
• W2895760106 cites W2032555072 @default.
• W2895760106 cites W2048255085 @default.
• W2895760106 cites W2050606799 @default.
• W2895760106 cites W2050896765 @default.
• W2895760106 cites W2052189407 @default.
• W2895760106 cites W2053131483 @default.
• W2895760106 cites W2064163449 @default.
• W2895760106 cites W2064627646 @default.
• W2895760106 cites W2066492413 @default.
• W2895760106 cites W2068585157 @default.
• W2895760106 cites W2076172469 @default.
• W2895760106 cites W2082625728 @default.
• W2895760106 cites W2084237334 @default.
• W2895760106 cites W2085261477 @default.
• W2895760106 cites W2085418183 @default.
• W2895760106 cites W2087586442 @default.
• W2895760106 cites W2091236571 @default.
• W2895760106 cites W2101762911 @default.
• W2895760106 cites W2104112226 @default.
• W2895760106 cites W2115357182 @default.
• W2895760106 cites W2123752261 @default.
• W2895760106 cites W2125872855 @default.
• W2895760106 cites W2125878976 @default.
• W2895760106 cites W2127596679 @default.
• W2895760106 cites W2128693624 @default.
• W2895760106 cites W2135319698 @default.
• W2895760106 cites W2135374912 @default.
• W2895760106 cites W2135802236 @default.
• W2895760106 cites W2140829266 @default.
• W2895760106 cites W2143259483 @default.
• W2895760106 cites W2143355874 @default.
• W2895760106 cites W2144036357 @default.
• W2895760106 cites W2144511940 @default.
• W2895760106 cites W2147240769 @default.
• W2895760106 cites W2153756342 @default.
• W2895760106 cites W2164365774 @default.
• W2895760106 cites W2165048205 @default.
• W2895760106 cites W2166357730 @default.
• W2895760106 cites W2177747623 @default.
• W2895760106 cites W2182554052 @default.
• W2895760106 cites W2184423371 @default.
• W2895760106 cites W2199984605 @default.
• W2895760106 cites W2298894722 @default.
• W2895760106 cites W2411561471 @default.
• W2895760106 cites W2488914148 @default.
• W2895760106 cites W2519763977 @default.
• W2895760106 cites W2563955570 @default.
• W2895760106 cites W2566621300 @default.
• W2895760106 cites W2581785783 @default.
• W2895760106 cites W2589778519 @default.
• W2895760106 cites W2605771209 @default.
• W2895760106 cites W2606170887 @default.
• W2895760106 cites W2609035396 @default.
• W2895760106 cites W2615587616 @default.
• W2895760106 cites W2742753960 @default.
• W2895760106 cites W2768045943 @default.
• W2895760106 cites W2771093031 @default.
• W2895760106 cites W2772563988 @default.
• W2895760106 cites W2775535358 @default.

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