Contribution of the precursors and interplay of the pathways in the phospholipid metabolism of the malaria parasite (original) (raw)

Journal of Lipid Research

lysophosphatidylcholine • lipidomics • tandem mass spectrometry • stable isotope tracers Malaria is a major global health problem, affecting more than 40% of the world's population. This disease is responsible for 196 million to 263 million annual cases, resulting in about 445,000 deaths, most of them occurring in children under the age of 5 in sub-Saharan Africa (1). Malaria is caused by parasites of the genus Plasmodium, and the most lethal human malaria parasite is Plasmodium falciparum. The parasite has a complex life cycle developing in mosquitos and humans, but all clinical features are caused during the repeated invasion of human red blood cells (RBCs). No efficient vaccine is currently available, and resistance to all available treatments has now been observed, making it urgent to identify novel pharmacological targets (1-3). The mature RBC is a very particular host cell for an intracellular parasite. RBCs do not contain organelles and are therefore capable of only few metabolic functions. After invasion, the parasite resides and develops within a parasitophorous vacuole and produces an extensive tubular membrane network in the erythrocyte cytoplasm. During its development, the parasite internalizes and digests the host cell hemoglobin (Hb) in a particular proteolytic Abstract The malaria parasite, Plasmodium falciparum, develops and multiplies in the human erythrocyte. It needs to synthesize considerable amounts of phospholipids (PLs), principally phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS). Several metabolic pathways coexist for their de novo biosynthesis, involving a dozen enzymes. Given the importance of these PLs for the survival of the parasite, we sought to determine their sources and to understand the connections and dependencies between the multiple pathways. We used three deuterated precursors (choline-d 9 , ethanolamine-d 4 , and serine-d 3) to follow and quantify simultaneously their incorporations in the intermediate metabolites and the final PLs by LC/MS/ MS. We show that PC is mainly derived from choline, itself provided by lysophosphatidylcholine contained in the serum. In the absence of choline, the parasite is able to use both other precursors, ethanolamine and serine. PE is almost equally synthesized from ethanolamine and serine, with both precursors being able to compensate for each other. Serine incorporated in PS is mainly derived from the degradation of host cell hemoglobin by the parasite. P. falciparum thus shows an unexpected adaptability of its PL synthesis pathways in response to different disturbances. These data provide new information by mapping the importance of the PL metabolic pathways of the malaria parasite and could be used to design future therapeutic approaches.