Trypanosoma brucei: a model micro‐organism to study eukaryotic phospholipid biosynthesis

Abstract

Although the protozoan parasite, Trypanosoma brucei, can acquire lipids from its environment, recent reports have shown that it is also capable of de novo synthesis of all major phospholipids. Here we provide an overview of the biosynthetic pathways involved in phospholipid formation in T. brucei and highlight differences to corresponding pathways in other eukaryotes, with the aim of promoting trypanosomes as an attractive model organism to study lipid biosynthesis. We show that de novo synthesis of phosphatidylethanolamine involving CDP‐activated intermediates is essential in T. brucei and that a reduction in its cellular content affects mitochondrial morphology and ultrastructure. In addition, we highlight that reduced levels of phosphatidylcholine inhibit nuclear division, suggesting a role for phosphatidylcholine formation in the control of cell division. Furthermore, we discuss possible routes leading to phosphatidylserine and cardiolipin formation in T. brucei and review the biosynthesis of phosphatidylinositol, which seems to take place in two separate compartments. Finally, we emphasize that T. brucei represents the only eukaryote so far that synthesizes all three sphingophospholipid classes, sphingomyelin, inositolphosphorylceramide and ethanolaminephosphorylceramide, and that their production is developmentally regulated.

Untargeted Metabolomics Reveals a Lack Of Synergy between Nifurtimox and Eflornithine against Trypanosoma brucei

“…Polyamines have previously been shown to be key mediators of membrane stability [34]–[36], and the lipid degradation observed here is consistent with cell membranes being compromised by polyamine depletion. Furthermore, the majority of metabolites in the cell decrease at the 48 hour time point, indicating a possibility that the cell membrane has been compromised and metabolites may be leaking from the cell during incubation and/or sample preparation.…”

“…Our studies indicate that eflornithine is trypanostatic for 48 hours, before killing the parasites after apparently compromising the membrane of the cell, as judged by a general loss of metabolites from the cell and particularly changes in lipid content. Since polyamines have been proposed to help stabilise membrane phospholipids [34], [35] this could indicate the actual cause of death following reduction in polyamine biosynthesis. In vivo , changes to membrane integrity would also expose new ligands to the immune systems, possibly explaining the need of an active immune system for optimal eflornithine activity [47].…”

Lipid Transport between the Endoplasmic Reticulum and Mitochondria

“…In the yeast, deletion of the only phosphatidylinositol synthase gene PIS1 is lethal (Nikawa et al 1987). Furthermore, PI serves as precursor for cell signaling molecules such as phosphatidylinositol phosphates (PIP), phosphatidylinositol bisphosphates (PIP2) and phosphatidylinositol triphosphates (PIP3) and for the biosynthesis of GPI anchors (Serricchio and Bütikofer 2011).…”

The Trypanosoma brucei dihydroxyacetonephosphate acyltransferase TbDAT is dispensable for normal growth but important for synthesis of ether glycerophospholipids

“…T . brucei membranes contain the typical phospholipids found in most eukaryotic cells, phosphatidylcholine being the most abundant (PC, 45–60%) followed by phosphatidylethanolamine (PE, 10–20%), phosphatidylinositol (PI, 6–12%), phosphatidylserine (PS, <4%), and cardiolipin (<3%) [2, 10, 11]. …”