Sphingolipids degradation

Kolter T, Sandhoff (2005) Principles of lysosomal membrane digestion stimulation of sphingolipid degradation by sphingolipid activator proteins and anionic lysosomal lipids. Annu Rev Cell Dev Biol 21 81-103... 

The polar lipids of membranes undergo constant metabolic turnover, the rate of their synthesis normally counterbalanced by the rate of breakdown. The breakdown of lipids is promoted by hydrolytic enzymes in lysosomes, each enzyme capable of hydrolyzing a specific bond. When sphingolipid degradation is impaired by a defect in one of these enzymes (Fig. 1), partial breakdown products accumulate in the tissues, causing serious disease. 

Tay-sachs disease A genetic disease caused by a deficiency of the lysosomal enzyme N-acetylhexosaminidase A, which is involved in sphingolipid degradation. The... 

Table 2. Inherited diseases caused by defective sphingolipid degradation ...

In the last step of sphingolipid degradation, ceramide is split into sphingosin and a long-chain fatty acid by the enzyme ceramidase. The genetic defect of this enzyme leads to Farber s disease, a storage disorder with onset in early childhood. In most cases, death occurs in the early years of life, but later-onset types with variable involvement of the central nervous system have also been observed. 

Not only the deficiency of a hydrolytic enzyme, but also of other proteins required for sphingolipid degradation can cause a sphingolipid storage disease. Besides deficiencies of activator proteins, this is the case in galactosialidosis. This disease is characterized by the secondary deficiency of P-galactosidase and sialidase activity. The primary defect is due to mutations within the protective protein, which forms a stable complex with the GMl-p-galactosidase and the lysosomal sialidase [47]. 

Linke, T., Wilkening, G., Sadeghlar,. F, MozcaU, H., Bernardo, K., Schuchman, E., and Sandhoff, K., 2001, Interfacial Regulation of Acid Ceramidase Activity. Stimulation of ceramide degradation by lysosomal lipids and Sphingolipid Activator Proteins. J. Biol. Chem. 276 5760-5768. 

Sphingolipids released when membrane is degraded are digested in endosomes after fusion with lysosomes. Lysosomes contain many enzymes, each of which removes specific groups from individual sphingolipids. Genetic deficiencies of many of these enzymes are known, and the diseases share some of the characteristics of I-cell disease discussed in Chapter 4. Table 1-16-1 summarizes these. 

Certain classes of lipids are susceptible to degradation under specific conditions. For example, all ester-linked fatty acids in triacylglycerols, phospholipids, and sterol esters are released by mild acid or alkaline treatment, and somewhat harsher hydrolysis conditions release amide-bound fatty acids from sphingolipids. Enzymes that specifically hydrolyze certain lipids are also useful in the determination of lipid structure. Phospholipases A, C, and D (Fig. 10-15) each split particular bonds in phospholipids and yield products with characteristic solubilities and chromatographic behaviors. Phospholipase C, for example, releases a water-soluble phosphoryl alcohol (such as phosphocholine from phosphatidylcholine) and a chloroform-soluble diacylglycerol, each of which can be characterized separately to determine the structure of the intact phospholipid. The combination of specific hydrolysis with characterization of the products by thin-layer, gas-liquid, or high-performance liquid chromatography often allows determination of a lipid structure. 

Degradation of sphingolipids showing the enzymes missing in related genetic diseases, the sphingolipidoses. All of the diseases are autosomal recessive except Fabry disease which is X-linked, and all can be fatal in early life. (Cer = ceramide). 

Sphingolipids as well as other membrane components are constantly degraded and resynthesized. 

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. 

Figure 9.20 Degradation of sphingolipids. Lipid storage diseases are indicated by brackets as follows TS, Tay-Sachs ML, metachromatic leukodystrophy GG, generalized gangliosidosis G, Gaucher s disease NP, Niemann-Pick disease K, Krabbe s disease F, Fabry s disease. The sulfate residue on galactocerebroside is located on position 3 of the galactose residue. Note the sequential nature of the process if one step cannot take place, all subsequent steps cannot take place, either.

Ferlinz, K., linke, T., Bartelsen, O., Weiler, M., and Sandhoff, K., 1999, Stimulation of lysosomal sphingomyelin degradation by sphingolipid activator proteins. Chem Phys Lipids 102 35-43. 

---