Sphingomyelin and ceramide metabolism

Sphingolipids are a class of lipids which possesses sphingoid bases such as sphingosine as backbone. Like other membrane phospholipids, sphingolipids are ampipathic possessing hydrophilic heads and hydrophobic tails. Sphingolipids are important in various cell signalling processes as first and second messengers including cell proliferation, differentiation and apoptosis in higher eukaryotes. They are also important constituents of lipid rafts of cell membranes. The simplest sphingolipids is ceramide which has very limited hydrophilicity as it only has 2 hydroxyl groups and no other polar groups are present. In addition to its role in signalling processes, it is also the precursor for the biosynthesis of other complex sphingolipids [1]. Animals possess two different types of these complex sphingolipids, which are sphiongophospholipids and glycosphingolipids respectively. The main sphingophospholipid in mammals is sphingomyelin. Sphingomyelin possesses a phosphocholine group attached to the ceramide backbone. The glycosphingolipids are molecules which have sugar residues attached to the ceramide backbone. The three different types of glycosphingolipids are cerebrosides (1 sugar moiety attached to hydroxyl-group in ceramide), globosides (more than 1 sugar groups attached to ceramide) and gangliosides (at least 1  N-acetylneuraminic acid residue is attached to the sugar chain). In contrast to animals, inositol phosphorylceramide is generated from ceramide in plants, fungi and kinetoplastids such as Trypanosoma and Leishmania [2].

 

The apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii can de novo synthesise sphingomyelin and glucosylceramide. In addition, they also utilise ceramide derived from host sphingolipids via the action of the enzyme sphingomyelinase (sphingomyelin phosphodiesterase). There are biochemical evidences available for P. falciparum to suggest the importance of both de novo synthesis [3, 4] and salvage [4, 5] mechanisms. The depletion of glucosylceramides and inhibition of intra-erythrocyte parasite growth with ceramide glucosyltransferase (glucosylceramide synthase) inhibitor threo-PPMP in P. falciparum suggests the importance of glucosylceramide synthesis [6].

 

The analysis of Piroplasma genomes shows that they possess the enzymes for the de novo synthesis of sphingomyelin and glucosylceramide from sphinganine. The sphingolipid desaturase, the oxidoreductase enzyme in the ceramide synthesis is missing in the gene models as in P. falciparum. There are two different enzymes which catalyse the synthesis of sphingomyelin from ceramide are present among apicomplexans. They are sphingomyelin synthase and ceramide cholinephosphotransferase. Of these sphingomyelin synthase is present in Theileria parva and Theileria annulata and ceramide cholinephosphotransferase is present in T. annulata and Babesia bovis. The enzyme sphingomyelinase catalysing salvage of host sphingomyelin into ceramide is also present in these Piroplasma species. These suggest that Piroplasma species can synthesise sphingomyelin in addition to the salvage from host.

 

Enzyme EC Number Gene id
Oxidoreductase 1.14.-.- Missing in annotation
Sphingosine N-acyltransferase 2.3.1.24 TP02_0395
Ceramide glucosyltransferase 2.4.1.80 TP02_0741
UTP-glucose-1-phosphate uridylyltransferase 2.7.7.9 TP01_0489
Sphingomyelin synthase 2.7.8.27 TP04_0631
Ceramide cholinephosphotransferase 2.7.8.3 Missing in annotation (Absent)
Sphingomyelin phosphodiesterase 3.1.4.12 TP01_1199
Long-chain-fatty-acid-CoA-ligase 6.2.1.3 TP01_0119
Long-chain-fatty-acid-CoA-ligase 6.2.1.3 TP01_0520
Long-chain-fatty-acid-CoA-ligase 6.2.1.3 TP02_0107
Neutral-sphingomyelinase activator none TP03_0409

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Sphinganine Host    
Fatty acid Host    
Glucose-1P Glycolysis Choline phosphate Phosphatidylcholine metabolism
Phosphatidylcholine Phosphatidylcholine metabolism 1,2-Diacylglycerol Phosphatidylethanolamine metabolism
Sphingomyelin Host Sphingomyelin/Glucosylceramide Membranes