Sphingomyelin and ceramide metabolism (salvage of sphingomyelin)

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 sphingolipid 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 Cryptosporidium muris genome shows that it possesses the enzymes for the de novo synthesis of ceramide. The sphingolipid desaturase, the oxidoreductase enzyme in the ceramide synthesis is missing in the gene models as in P. falciparum. Although the enzymes for ceramide and glucosylceramide synthesis are present, the enzymes which catalyse synthesis of sphingomyelin from ceramide such as sphingomyelin synthase and ceramide cholinephosphotransferase are absent in C. muris. The enzyme sphingomyelinase catalysing salvage of host sphingomyelin into ceramide is also present. This suggests that C. muris can only acquire sphingomyelin from host and cannot synthesise de novo. In contrast, the Cryptosporidium species that infect the epithelial cells of small intestine such as C. parvum and C. hominis do not possess the enzymes for the de novo synthesis of ceramide from fatty acids. They possess sphingomyelinase and glucosylceramide synthase enzymes suggesting the ability to salvage host sphingomyelin and convert them to ceramide and glucosylceramide. This suggests that inhibition of the enzyme glucosylceramide is a potential drug target for Cryptosporidium infections.

 

Enzyme EC Number Gene id
3-dehydrosphinganine reductase 1.1.1.102 Absent
Oxidoreductase 1.14.-.- Absent
Sphingosine N-acyltransferase 2.3.1.24 Absent
Serine C-palmitoyltransferase 2.3.1.50 Absent
Ceramide glucosyltransferase 2.4.1.80 cgd5_2040
UTP-glucose-1-phosphate uridylyltransferase 2.7.7.9 cgd4_810
Sphingomyelin phosphodiesterase 3.1.4.12 cgd6_2290
Long-chain-fatty-acid-CoA ligase 6.2.1.3 cgd3_640
Long-chain-fatty-acid-CoA ligase 6.2.1.3 cgd4_3400
Long-chain-fatty-acid-CoA ligase 6.2.1.3 cgd5_3200
Neutral-sphingomyelinase activator none cgd4_3390
Glycolipid transfer protein none cgd5_3550

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Glucose-1P Glycolysis Choline phosphate Phosphatidylcholine metabolism
Sphingomyelin Host Glucosylceramide Membranes