Phosphatidylethanolamine and phosphatidylserine metabolism

Phospholipids are crucial components of the cell membrane bilayers. Most of these phospholipids are composed of a diglyceride (diacylglycerol) moiety, a phosphate group and a simple organic molecule such as choline, serine or ethanolamine. The anionic phosphate group and polar groups such as choline forms the hydrophilic head and the fatty acid chains in diacylglycerol forms the hydrophobic tails in the membrane bilayer. Phosphatidic acids with ethanolamine and serine attached are referred to as phosphatidylethanolamine (cephalin) and phosphatidylserine respectively. Phosphatidylethanolamine is found in all living cells and it is the principal phospholipid in bacteria.

 

Toxoplasma gondii can de novo synthesise phospholipids such as phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine. Gupta et al has quantified the composition of different phospholipids in free T. gondii parasites. According to this, the most abundant phospholipid is phosphatidylcholine (75%) and it is followed by phosphatidylethanolamine (10%). Other phospholipids quantified are phosphatidylinositol (7.5%), phosphatidylserine (6%) and phosphatidate (1%) [1]. The labelling experiments showed that phosphatidylserine and phosphatidylethanolamine can be produced from serine in extracellular parasites. In addition, phosphatidylethanolamine can be synthesised from ethanolamine acquired from extracellular type medium in the parasites. The rate of synthesis of these phospholipids did not change between extracellular type and intracellular type media. The measurement of activities of important enzymes of phosphatidylserine and phosphatidylethanolamine biosynthesis was measured. This suggested that phosphatidylserine synthase in T. gondii catalyses the reaction via base (simple molecule group) exchange and the activity is dependent on ca2+ and phospholipids rather than on CDP-diacylglycerol. In addition, the inclusion of phosphatidylethanolamine in reaction has led to 6-8 fold increase in phosphatidylserine synthesis. This suggests that phosphatidylethanolamine provides phosphatidyl moiety and the enzyme replaces ethanolamine residue with serine leading to base-exchange based phosphatidylserine biosynthesis. Phosphatidylserine decarboxylase showed 200-fold higher activity in comparison to other key enzymes studied and 10-fold higher activity than phosphatidylserine decarboxylase enzymes from other species. In addition, the activity of ethanolamine phosphotransferase confirmed the presence of phosphatidylethanolamine generation from ethanolamine (acquired from external medium) [1].

 

The enzymes which belong to the catabolism branch of phosphatidylethanolamine metabolism are also present in T. gondii. Although, the enzyme phosphatidylethanolamine N-methyltransferase (2.1.1.17, produces monomethyl-phosphatidylethanolamine) is present, the enzyme phosphatidyl-N-methylethanolamine N-methyltransferase (2.1.1.71) which leads to synthesis of phosphatidylcholine is absent. The enzymes 2.1.1.17  and 2.1.1.71 are absent in Plasmodium falciparum. According to MPMP annotation, the phosphatidylserine synthase present in P. falciparum is CDP-diacylglycerol serine-O-phosphatidyltransferase (2.7.8.8). This is one of the main differences between Plasmodium and Toxoplasma as Toxoplasma possesses base-exchange phosphatidylserine synthase (2.7.8.29). The enzymes involved in cardiolipin biosynthesis are present in both T. gondii and P. falciparum.

 

Protein EC Number Gene id Protein localisation Localisation data source
Phosphatidylethanolamine N-methyltransferase 2.1.1.17 TGME49_247590 Extracellular? Previous publication
Glycerol-3-phosphate O-acyltransferase 2.3.1.15 TGME49_203570    
Glycerol-3-phosphate O-acyltransferase 2.3.1.15 TGME49_256980 Plasma membrane Previous publication
Glycerol-3-phosphate O-acyltransferase 2.3.1.15 TGME49_270910 Apicoplast Orthology transformation from P. falciparum
Diacylglycerol O-acyltransferase 2.3.1.20 TGME49_226370    
Diacylglycerol O-acyltransferase 2.3.1.20 TGME49_232730    
Diacylglycerol O-acyltransferase 2.3.1.20 TGME49_275600    
1-Acylglycerol-3-phosphate O-acyltransferase 2.3.1.51 TGME49_240860 Apicoplast Previous publication
1-Acylglycerol-3-phosphate O-acyltransferase 2.3.1.51 TGME49_297640    
Diacylglycerol kinase 2.7.1.107 TGME49_202460 Nucleus Previous publication
Diacylglycerol kinase 2.7.1.107 TGME49_239250 Apicoplast Previous publication
Diacylglycerol kinase 2.7.1.107 TGME49_259830    
Ethanolamine kinase 2.7.1.82 TGME49_265000    
Ethanolamine kinase 2.7.1.82 TGME49_306540 Nucleus Previous publication
Ethanolamine-phosphate cytidylyltransferase 2.7.7.14 TGME49_310280    
Phosphatidate cytidylyltransferase 2.7.7.41 TGME49_263785    
Phosphatidate cytidylyltransferase 2.7.7.41 TGME49_281980    
Cardiolipin synthetase 2.7.8.- TGME49_309940 Nucleus Previous publication
Ethanolaminephosphotransferase 2.7.8.1 TGME49_257510    
Ethanolaminephosphotransferase 2.7.8.1 TGME49_261760    
L-serine-phosphatidylethanolamine phosphatidyltransferase (phosphatidylserine synthase 2) 2.7.8.29 TGME49_261480    
L-serine-phosphatidylethanolamine phosphatidyltransferase (phosphatidylserine synthase 2) 2.7.8.29 TGME49_273540 Plasma membrane Previous publication
CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase 2.7.8.5 TGME49_246530    
Triacylglycerol lipase 3.1.1.3 TGME49_254330    
Triacylglycerol lipase 3.1.1.3 TGME49_262400 Extracellular? Previous publication
Triacylglycerol lipase 3.1.1.3 TGME49_269300    
Triacylglycerol lipase 3.1.1.3 TGME49_293240    
Phospholipase A2 3.1.1.4 TGME49_231370    
Phospholipase A2 3.1.1.4 TGME49_254420    
Phospholipase A2 3.1.1.4 TGME49_305140 Nucleus Previous publication
Phospholipase A2 3.1.1.4; 3.1.1.3 TGME49_212130 Plasma membrane Previous publication
Lysohospholipase 3.1.1.5 TGME49_226390    
Lysohospholipase 3.1.1.5 TGME49_306330 Cytosol Previous publication
Phosphatidylglycerophosphatase 3.1.3.27 Missing in annotation    
Phospholipase C 3.1.4.3 TGME49_248830 Plasma membrane; Nucleus? Apiloc; Previous publication
Glycerophosphodiester phosphodiesterase 3.1.4.46 TGME49_256090 Mitochondrion Previous publication
Glycerophosphodiester phosphodiesterase 3.1.4.46 TGME49_263270 Plasma membrane Previous publication
Phosphatidylserine decarboxylase 4.1.1.65 TGME49_225550 Apicoplast Previous publication
Phosphatidylserine decarboxylase 4.1.1.65 TGME49_269920 Cytosol Previous publication
Acyl-CoA synthetase 6.2.1.3 TGME49_043800 Cytosol Previous publication
Acyl-CoA synthetase 6.2.1.3 TGME49_247760 Mitochondrion Previous publication
Acyl-CoA synthetase 6.2.1.3 TGME49_297220    
Acyl-CoA synthetase 6.2.1.3 TGME49_310080 Cytosol Previous publication
Acyl-CoA synthetase 6.2.1.3 TGME49_310150 Mitochondrion Previous publication
Phosphatidylethanolamine binding protein none TGME49_207930 Extracellular Previous publication
Acyl-CoA binding protein none TGME49_234510    
MSF-1 none TGME49_254250    

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Ethanolamine Host O-Phosphoethanolamine Phosphatidylcholine metabolism
Fatty acid Fatty acid biosynthesis in the apicoplast, Fatty acid elongation in the cytosol, Fatty acid elongation in the ER, Host Cardiolipin Inner mitochondrial membrane
Glycerol-3P Glycolysis Triacylglycerol Recycling of phospholipids, Storage in lipid bodies
Serine Glycine, serine and cysteine metabolism Monomethyl-phosphatidylethanolamine ?
S-adenosylmethionine Methionine metabolism S-adenosylhomocysteine Methionine metabolism