Defining the minimal enzymatic requirements for fatty acid scavenging from lysophosphatidylcholine by erythrocytic Plasmodium falciparum.

Host-derived lysophosphatidylcholine (LPC) is a significant source of choline and fatty acids for the intraerythrocytic malaria parasite Plasmodium falciparum. Two lysophospholipases play a dominant role in LPC catabolism: exported lipase 2 (XL2) and exported lipase homolog 4 (XLH4). Loss of these two enzymes greatly reduces, but does not abrogate, the parasite's ability to utilize LPC as a source of fatty acids. In this study, we identify a third enzyme, termed "prodrug activation and resistance esterase" (PARE), that mediates low levels of LPC hydrolysis. Loss of PARE alone had no effect on the parasite's ability to scavenge fatty acids from LPC. However, when combined with the loss of XL2 and XLH4, knockdown of PARE impacted the parasite's ability to scavenge both choline and fatty acids from LPC. Furthermore, PARE/XL2/XLH4-deficient parasites were unable to complete a replication cycle when cultured in defined media with LPC as the sole source of exogenous fatty acids. We show that PARE is a membrane-associated enzyme with a substantial presence at the parasite periphery and propose a model whereby PARE catalyzes the hydrolysis of inwardly-diffusing LPC. Our findings reveal that asexual P. falciparum is dependent on parasite-encoded enzymes for LPC catabolism and rule out host erythrocyte enzymes as a physiologically-relevant source of lysophospholipase activity.