Sphingolipids degradation, defective

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. 

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]. 

Tay-Sachs disease. A member of a family of disorders identified as the Gm2 gangliosidoses. As neural cell membranes are enriched in Gm2 gangliosides, the inability to degrade this class of sphingolipid resnlts in neural cell death. In addition to Tay-Sachs disease the family includes the Sandhoff diseases and the Gm2 activator deficiencies. Tay-Sachs disease resnlts from defects in the HEXA gene encoding the a-subunit of /3-hexosaminidase. 

These analytical findings can be explained on the bases of the enzymatic defect in Sandhoff disease. P-Hexosaminidase p subunit is genetically defective in this disorder. Therefore, both hexosaminidase A (aP) and B (PP) isozymes are equally deficient ( total hexosaminidase deficiency ). While hexosaminidase S (aa) does exist, it is catalytically inactive toward natural substrates. The end result is the inability to degrade all natural sphingolipid and glycoprotein substrates beyond the stage where the next step is removal of a hexosamine residue. 

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