Sphingolipids catabolism

Glycosphingolipids Function as Structural Components and as Specific Cell Receptors Defects in Sphingolipid Catabolism Are Associated with Metabolic Diseases... 

Defects in Sphingolipid Catabolism Are Associated with Metabolic Diseases... 

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. 

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.

Furst W, Sandhoff K. Activator proteins and topology of lysosomal sphingolipid catabolism. Biochim. Biophys. Acta 1992 1126 1-16. 

Saposins, a family of four small heat-stable glycoproteins derived from the large precursor protein prosaposin (70 kDa). The saposins A-D are involved as cofactors in sphingolipid catabolism [Y. Kishimoto et al, J. Lipid Res. 1992, 33, 1255 A. M. Vaccaro et al., Neurochem. Res. 1999, 24, 307]. 

Sphingolipid breakdown is reviewed by Kanfer and Hakomori (1983) and deficiency diseases of sphingolipid catabolism are covered in Section 12.5. 

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

Usually each of the catabolic enzymes is specific for a particular chemical bond. Thus, a combination of a number of enzymes is needed to ensure the complete breakdown of a given sphingolipid. Catabolism begins by attack on the terminal hydrophilic portions of the molecules. The enzymes responsible are glucosidases, galactosidases, hexosaminidases. 

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

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.

Sphingolipids were first described in a remarkable treatise on the chemical constitution of the brain by Johann L. W. Thudichum, a physician-scientist in London, who published his findings more than 100 years ago. A major impetus for the study of the chemistry and metabolism of the sphingolipids was the discovery of several rare human diseases that could be attributed to the abnormal accumulation of sphingolipids. This accumulation has been shown to result from a defect in catabolism that normally occurs in lysosomes. It is now known that many different kinds of sphingolipids exist, and more than 300 structures have been reported to occur in nature. 

Lipids have several important functions in animal cells, which include serving as structural components of membranes and as a stored source of metabolic fuel (Griner et al., 1993). Eukaryotic cell membranes are composed of a complex array of proteins, phospholipids, sphingolipids, and cholesterol. The relative proportions and fatty acid composition of these components dictate the physical properties of membranes, such as fluidity, surface potential, microdomain structure, and permeability. This in turn regulates the localization and activity of membrane-associated proteins. Assembly of membranes necessitates the coordinate synthesis and catabolism of phospholipids, sterols, and sphingolipids to create the unique properties of a given cellular membrane. This must be an extremely complex process that requires coordination of multiple biosynthetic and degradative enzymes and lipid transport activities. 

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. 

Sphingolipids are in a continuous state of turnover. They are catabolized by lysosomal enzymes by stepwise removal of sugar residues beginning at the nonreducing end... 

Fig. lO. Catabolism of complex sphingolipids and diseases associated with deficiencies in the enzymes (modified from T. Kolter and K. Sandhoff, 2006). Abbreviations are as in the text. 

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