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.
Highlights
The finding that lyso-PC plays an important role in parasite development, differentiation, and transmission makes the metabolic pathways and the involved enzymes very attractive targets for antimalarial drugs
Identification and development of new classes of inhibitors that target essential steps in membrane biogenesis
Summary
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. 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 [24, 27, 28]. 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 [22, 30] PE metabolism has been implicated in important cellular processes such as autophagy, signaling, and viral replication (66 –70) and in human diseases such as Alzheimer’s disease, Parkinson’s disease, and nonalcoholic liver disease [71].The biosynthesis of PE in Plasmodium parasites
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