Contribution of the precursors and interplay of the pathways in the phospholipid metabolism of the malaria parasite

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-d9, ethanolamine-d4, and serine-d3) 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.

A patatin‐like phospholipase functions during gametocyte induction in the malaria parasite Plasmodium falciparum

“…Under normal serum conditions, PC is generated de novo from precursors by the cytidine diphosphate (CDP)-choline (Kennedy) pathway (reviewed in Tischer, Pradel, Ohlsen, & Holzgrabe, 2012;Flammersfeld et al, 2018). This pathway involves the activity of PMT and parasite lines deficient of PMT die in serum lacking these precursors (Wein et al, 2018). This pathway involves the activity of PMT and parasite lines deficient of PMT die in serum lacking these precursors (Wein et al, 2018).…”

“…Particularly, low serum levels of lysoPC, which was recently shown to act as the main exogenous precursor of PC, cause the blood stage parasites to enter the sexual pathway, among others initiated by the upregulation of ap2-g expression (Brancucci et al, 2017). Despite previous assumptions that choline is acquired from serum, new data indicate that the majority of choline to be incorporated in PC is generated from serum-imported lysoPC (Wein et al, 2018; Figure 6).…”

“…In the absence of lysoPC in the serum, however, PC is mainly synthesised via triple-methylation of phos-phoethanolamine using ethanolamine (from serum) or serine (from hemoglobin) as external precursors ( Figure 6). This pathway involves the activity of PMT and parasite lines deficient of PMT die in serum lacking these precursors (Wein et al, 2018). This alternative route of PC synthesis via the PMT pathway appears to be upregulated during sexual commitment due to lysoPC depletion, as shown by increased transcript synthesis of PMT and S-adenosylmethionine (SAM) synthetase under these conditions (Brancucci et al, , 2017.…”

“…Gametocyte induction is upregulated in response to stress factors and particularly depends on the availability of PC precursors in the human serum, that is, low levels of serum-derived lysoPC and choline cause the blood stage parasites to enter the sexual pathway (Brancucci et al, 2017;Wein et al, 2018). Gametocyte induction is upregulated in response to stress factors and particularly depends on the availability of PC precursors in the human serum, that is, low levels of serum-derived lysoPC and choline cause the blood stage parasites to enter the sexual pathway (Brancucci et al, 2017;Wein et al, 2018).…”

“…During the erythrocytic infection cycle, a proportion of blood stage parasites enter the sexual pathway, which results in the production of the transmissible gametocytes. Gametocyte induction is upregulated in response to stress factors and particularly depends on the availability of PC precursors in the human serum, that is, low levels of serum-derived lysoPC and choline cause the blood stage parasites to enter the sexual pathway (Brancucci et al, 2017;Wein et al, 2018). These gametocytes, once matured, transform into gametes following their uptake by blood-feeding Anopheles mosquitoes.…”