Lysosomal Transporters and Associated Diseases

Abstract

The lysosomal organelle system is the main vacuolar site for the turnover of endogenous and exogenous macromolecules. The lysosomal lumen contains a large number of pre dominantly hydrolytic enzymes for these catabolic steps with characteristic acidic pH-optima and high substrate specificity. The lysosomal membrane is formed by a typical single phospholipid bilayer which controls the passage of material into and out of lysosomes, by its permeability and ability to fuse with other (digestive) vacuoles. By the late seventies it became clear that the lysosomal membrane plays an important role in the disposal of metabolites produced by enzymatic degradation of macromolecules inside the lysosomal compartment. Initially the lysosomal membrane was considered to be only a mechanical border separating the acid lysosomal environment from the neutral surrounding cytoplasm. Since the discovery of a lysosomal cystine carrier, defective in an inherited human disease, more than 20 specific transport systems have been characterized in the lysosomal membrane. Most of them function as exporters and only a few as importers. Several types of lysosomal membrane transporters can be discriminated: solute carriers, pumps and channels. Each of the lysosomal transporters has a high specificity for groups of amino acids, sugars, nucleosides, inorganic ions, and vitamins. Genetic disorders of these transporters cause a wide array of neurological and visceral diseases, ranging from developmental to degenerative disorders. Until recently, all knowledge about lysosomal transport proteins was based on the biochemical (kinetic) characteristics of transport. For biochemical and kinetic properties regarding each system, readers are referred to previous reviews. The molecular and functional properties of the better characterized lysosomal transport systems and the related human diseases are discussed here.