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  • The lysosomal degradation of sphingolipids with short hydrophilic head groups is dependent on small nonenzymic glycoproteins, called sphingolipid activator proteins (SAPs), including saposins (Saps) and the GM2 activator protein.

  • Two genes code for all established and putative SAPs known so far. One gene on human chromosome 5, consisting of 4 exons and 3 introns, encodes the GM2 activator protein; a second gene on chromosome 10, consisting of 15 exons and 14 introns, codes for the prosaposin, which is processed to four homologous activator proteins or saposins, Sap-A, Sap-B, Sap-C, and Sap-D.

  • The mature human GM2 activator consists of a polypeptide chain of 162 amino acids and carries one N-linked carbohydrate chain on Asn 32. It is a membrane-active protein that binds structurally related glycosphingolipids and stimulates their degradation by a specific interaction with β-hexosaminidase A. This activator is essential for the hydrolysis of ganglioside GM2 and glycolipid GA2 in vivo.

  • Four point mutations have been identified so far in the GM2 activator gene in AB variant of GM2 gangliosidosis. They result in premature degradation of the GM2 activator and cause a pronounced neuronal storage of ganglioside GM2 and glycolipid GA2. The clinical course and pathologic findings observed in AB variant closely resemble those of Tay-Sachs disease.

  • The prosaposin (Sap precursor), with a total of 524 amino acids and five N-glycosylation sites, contains four homologous domains, each of about 80 amino acids. A major proportion of the precursor pool is exported to the cell surface and then imported into the lysosomal compartment, where it is processed to the mature glycoproteins Sap-A, Sap-B, Sap-C, and Sap-D. The occurrence of prosaposin in body fluids and its neurotrophic properties indicate that its function is not restricted to being the precursor of the mature intracellular Saps.

  • In vitro, Sap-A stimulates glucosylceramidase and galactosylceramidase in the presence of detergents; this determination is supported by studies in a conditional knock-out mouse model.

  • Sap-B is a nonspecific glycolipid-binding protein that stimulates the hydrolysis of about 20 glycolipids by different enzymes, in particular the hydrolysis of sulfatide by arylsulfatase A.

  • So far, seven different mutations have been identified in the stretch of the prosaposin gene coding for Sap-B. They result in a loss of the mature Sap-B, causing the accumulation of sulfatide and some other sphingolipids. The clinical course of the disease resembles that of juvenile metachromatic leukodystrophy, with certain exceptions.

  • In vitro, Sap-C stimulates the hydrolysis of glucosylceramide by glucosylceramidase, galactosylceramide by galactosylceramidase, and sphingomyelin by acid sphingomyelinase. In vivo, Sap-C is essential for the degradation of glucosylceramide. The Sap-C glycoprotein factor has been proposed to bind to, and thereby activate, glucosylceramidase. It is a membrane-active protein that solubilizes lipids. Deficiency of Sap-C results in a juvenile variant of Gaucher disease, with pronounced accumulation of glucosylceramide in the reticuloendothelial system. Sap-C seems to have a role also in galactolipid breakdown.

  • Sap-D has a lipid membrane-disrupting activity ...

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