[Lysosomal enzymes, sphingolipid activator proteins, and protective protein]

The lysosome is an intracytoplasmic acidic vacuole containing more than 60 hydrolytic enzymes for digestion of macromolecules, such as nucleic acids, proteins, lipids and complex carbohydrates. Expression of lysosomal enzyme activities is regulated by various intracellular environmental factors. Mutation of a gene coding for a lysosomal enzyme results in a specific genetic disease, often involving the central nervous system in children. Three groups of functional proteins are known at present for regulation of the expressed enzyme activity in lysosomes. Targeting of a newly synthesized protein is achieved by the mannose 6-phosphate receptor system, which was revealed in the course of I -cell disease research. Many lysosomal enzymes are excessively secreted in the extracellular compartment in the absence of this regulatory system in patients with this disease. Intralysosomal stability of beta-galactosidase is regulated by a multifunctional protein that interacts with two lysosomal enzymes, beta-galactosidase and sialidase, and also exerts catalytic activities as carboxypeptidase, esterase and deamidase under various pH conditions. It is encoded by a gene on chromosome 20, and its mutation results in a neurodegenerative disease in children and adults (galactosialidosis). For digestion of lipid substrates, lysosomal enzymes need specific activator proteins as natural detergents for molecular interaction with these nonpolar compounds. Two different groups of proteins have been revealed. A protein encoded by a gene on chromosome 5 interacts with ganglioside GM2 and its asialo derivative, for their catalytic hydrolysis by beta-hexosaminidase A. Another protein encoded by a gene on chromosome 10 is expressed as a precursor (prosaposin) which is then processed to four small proteins (saposins) with heterogeneous functions. They are essential for hydrolysis of sphingolipid substrates, and genetic deficiency of each protein results in various lipid storage diseases.