Role of phospholipid synthesis in the development and differentiation of malaria parasites in the blood

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.

Keywords: development; differentiation; malaria; phospholipid metabolism; plasmodium.

Figure 1.

Lipid synthetic pathways in the asexual stages of Plasmodium. The following abbreviations are used: RBCM, red blood cell membrane; RBCC, red blood cell cytosol; PPM, parasite plasma membrane; DV, digestive vacuole; HZ, hemozoin; P/AA, peptides and amino acids; PfPSS, P. falciparum PS synthase; PfSD, P. falciparum serine decarboxylase (asterisk indicates that enzyme activity has been reported but no corresponding gene has been identified); PfPLC, P. falciparum phospholipase C; PfPSD, P. falciparum PS decarboxylase; PfCT, P. falciparum choline transporter; PfCK, P. falciparum choline kinase; PfCCT, P. falciparum CTP:phosphocholine cytidylyltransferase; PfCEPT, P. falciparum choline/ethanolamine-phosphotransferase; PfPMT, P. falciparum phosphoethanolamine methyltransferase; LD-PLC, lyso-PC–dependent phospholipase C; PfNSM, P. falciparum neutral sphingomyelinase; LD-PLD, lyso-PC–dependent phospholipase D. Dashed arrows represent putative routes of transport and metabolism. The “?” indicates pathways and enzymes that might exist or catalyze certain reactions respectively but that have not been identified yet.