Sphingolipid catabolism, pathway

Interestingly, all of the enzymes that comprise the sphingolipid-catabolic pathway are glycoproteins and may be found in different places within the organelle. For example, glucocerebrosidase is firmly associated with the lysosomal membrane, whereas others, like hexoseaminidase A, exist largely in soluble form in the lysosomal matrix. A common property of the lysosomal hydrolases, however, is their expression of maximum activity at a relatively acidic pH (i.e., pH 4.0-5.5), hence the term acid hydrolase. This is not unexpected because ATP-driven proton pumps sustain an acidic milieu (pH 5.2) within the lysosome. 

Acid CDase is localized in the lysosomes and it is suggested that it plays an important role in the catabolic pathway of sphingolipids. It has been also suggested recently, to play a role in apoptosis in response to TNFa induced death ofL929 cells (Strelow etal, 2000). 

Figure 21-6 Pathways of synthesis and metabolism of sphingolipids. Gray arrows indicate catabolic pathways. See also Fig. 20-11. The green extension on the ceramide structure is that of a long-chain co-hydroxyceramide that is covalently bound to protein in human skin.

Figure 16-5. The pathway of sphingolipid catabolism. Diseases that result from specific enzyme deficiencies are as follows (1) GM, gangliosidosis (2) GM2 gangliosidosis (Tay-Sachs disease) (3) sialidosis (4) Fabry disease (5) Gaucher disease (6) Niemann-Pick disease (7) Krabbe disease (8) metachromatic leukodystrophy (9) Farber disease. Cer, Ceramide Glc, glucose Gal, galactose GalNAc, A -acetylgalactosamine NANA, N-acetyfiieuraminic acid.

Palmitic acid i Etbanolamine phosphate Fig. 3. Pathways of sphingolipid catabolism. 

Figure 7.15 Pathways for sphingolipid catabolism showing enzyme deficiencies in lipid storage diseases.

Synthesis of glycosphingolipids and sulfoglycosphin-golipids involves the addition of sugar and sulfate residues to ceramide from UDP-sugar derivatives or the activated sulfate donor 3 -phosphoadenosine-5 -phosphosulfate (Chapter 17), and appropriate transferases. These pathways are discussed in Chapter 16. Catabolism of sphingolipids is by specific lysosomal hydrolases. Several inherited disorders associated with the deficiencies of these enzymes are discussed below. 

Phosphatidylethanolamine can be formed in four ways (Table 7.2). Again, the CDP-ethanolamine pathway is the most active pathway in animals and plants. However, the ethanolamine which is needed for this pathway derives from the decarboxylation of serine and that reaction can only, apparently, take place on a lipid substrate (i.e. phosphatidylserine) in animal tissues. Thus the decarboxylation of phosphatidylserine (method 2) assumes importance not only as a source of phosphatidylethanolamine directly but also to provide ethanolamine. In addition, ethanolamine can be liberated by the catabolism of sphingolipids. The decarboxylation of phosphatidylserine is the method by which bacteria produce phosphatidylethanolamine. The other two pathways (methods 3 and 4) are of minor overall significance but may be used for specialist purposes, e.g. method 4 is used for the formation of molecular species which are poorly formed by the CDP-base pathway. 

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