Lipid Metabolism in Plasmodium falciparum

Plasmodium falciparum relies on tightly regulated lipid metabolism to sustain its complex life cycle within human erythrocytes. Rapid parasite replication demands extensive membrane biogenesis, achieved through a combination of de novo phospholipid synthesis, host lipid scavenging and selective lipid remodelling. Major phospholipids—phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine—are synthesised via distinct enzymatic pathways, including the CDP-choline route and the serine-decarboxylase-phosphoethanolamine-methyltransferase pathway. Concurrently, an array of parasite phospholipases and lipid-remodelling enzymes modulate membrane composition, signalling lipids and organelle biogenesis. Host-derived cholesterol and sphingolipids are incorporated and trafficked to parasite compartments, while neutral lipid stores buffer fluctuations in nutrient availability. Lipidomic profiling has revealed stage-specific shifts in glycerophospholipid, sphingolipid and sterol content, highlighting critical nodes for therapeutic intervention. Understanding these interconnected processes is essential for identifying novel drug targets and for elucidating mechanisms of antimalarial resistance.

Research from Nature Portfolio

Advanced live-cell imaging has elucidated how the host erythrocyte membrane is remodelled and repurposed during parasite invasion. Using four-dimensional lattice light-sheet microscopy, researchers demonstrated that the parasitophorous vacuole membrane is predominantly derived from host lipid bilayers and undergoes dynamic biophysical changes driven by parasite-secreted lipids and proteins. Separately, the identification of a parasite prodrug-activating esterase revealed its central role in hydrolysing esterified compounds. This enzyme, essential for conversion of lipid-based prodrugs into active forms, underscores how parasite lipid-processing machinery can determine drug efficacy and resistance profiles.

Lipid Metabolism in Plasmodium falciparum publication trend

The graph below shows the total number of articles in lipid metabolism in plasmodium falciparum across all publications each year (not limited to Nature Index journals).

Technical terms

Phosphoinositide-specific phospholipase C (PI-PLC): Enzyme that hydrolyses phosphatidylinositides into diacylglycerol and inositol phosphates, regulating membrane composition and signalling.

Lysobisphosphatidic acid (LBPA): An anionic phospholipid produced from phosphatidylglycerol, implicated in membrane curvature, trafficking and organelle biogenesis.

Patatin-like phospholipase (PNPLA2): Lipid-remodelling enzyme with acyl-hydrolase activity, involved in the degradation of specific phospholipids within organelles.

Sphingosine-1-phosphate (S1P): Bioactive sphingolipid mediator formed by sphingosine kinase, which influences cell signalling and epigenetic modulation.

Histone deacetylase (HDAC): Enzyme that removes acetyl groups from histone tails, altering chromatin structure and controlling gene expression.

Parasitophorous vacuole membrane (PVM): Host-derived lipid bilayer enveloping the intracellular parasite, essential for nutrient import and immune evasion.

References

1. Global analysis of putative phospholipases in Plasmodium falciparum reveals an essential role of the phosphoinositide-specific phospholipase C in parasite maturation. mBio (2023).
2. The patatin-like phospholipase PfPNPLA2 is involved in the mitochondrial degradation of phosphatidylglycerol during Plasmodium falciparum blood stage development. Frontiers in Cellular and Infection Microbiology (2023).
3. Host-Erythrocytic Sphingosine-1-Phosphate Regulates Plasmodium Histone Deacetylase Activity and Exhibits Epigenetic Control over Cell Death and Differentiation. Microbiology Spectrum (2023).
4. 4D analysis of malaria parasite invasion offers insights into erythrocyte membrane remodeling and parasitophorous vacuole formation. Nature Communications (2021).
5. Esterase mutation is a mechanism of resistance to antimalarial compounds. Nature Communications (2017).
6. 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*. Journal of Biological Chemistry (2008).
7. Contribution of the precursors and interplay of the pathways in the phospholipid metabolism of the malaria parasite. Journal of Lipid Research (2018).
8. Changes in lipid composition during sexual development of the malaria parasite Plasmodium falciparum. Malaria Journal (2016).
9. Inward cholesterol gradient of the membrane system in P. falciparum-infected erythrocytes involves a dilution effect from parasite-produced lipids. Biology Open (2014).