Carbohydrate-Processing Enzymes of the Lysosome: Diseases Caused by Misfolded Mutants and Sugar Mimetics as Correcting Pharmacological Chaperones.

Lysosomal storage diseases are hereditary disorders caused by mutations on genes encoding for one of the more than fifty lysosomal enzymes involved in the highly ordered degradation cascades of glycans, glycoconjugates, and other complex biomolecules in the lysosome. Several of these metabolic disorders are associated with the absence or the lack of activity of carbohydrate-processing enzymes in this cell compartment. In a recently introduced therapy concept, for susceptible mutants, small substrate-related molecules (so-called pharmacological chaperones), such as reversible inhibitors of these enzymes, may serve as templates for the correct folding and transport of the respective protein mutant, thus improving its concentration and, consequently, its enzymatic activity in the lysosome. Carbohydrate-processing enzymes in the lysosome, related lysosomal diseases, and the scope and limitations of reported reversible inhibitors as pharmacological chaperones are discussed with a view to possibly extending and improving research efforts in this area of orphan diseases.