Gangliosides are components of the plasma membrane and their metabolism consists in: de novo biosynthesis, occurring mostly in the Golgi apparatus; catabolism, taking place in the lysosomes; salvage processes (re-cycling of catabolites) with the coordinate participation of lysosomes, endoplasmic reticulum and Golgi apparatus; glycosylation of internalized gangliosides, taking place in the Golgi apparatus. The various steps of ganglioside metabolism are intimately connected with the rapid events of membrane turnover, and occur rapidly themselves. Gangliosides do undergo endocytosis and move from the early endosome compartment partly to the Golgi apparatus, partly to late endosomes and lysosomes. Direct return of gangliosides to the plasma membrane via retro-endocytosis or transport, mediated by carrier proteins, has not yet been explored. Intralysosomal biodegradation of gangliosides leads to formation of sphingosine and ceramide, substances that behave as powerful metabolic regulators. The process appears to be influenced by agents that modify the functional state of the cell. The hypothesis is released that factors capable to affect ganglioside endocytosis do affect the rate of ganglioside metabolic processing, thus changing the concentration of second messengers of sphingoid nature.
A family of proteoglycans (PGs) originally known as “small proteoglycans” has recently been defined. The members of the family are decorin, biglycan, fibromodulin and lumican. All are indeed small for proteoglycans with core proteins of approximately 40kDa; they are made up of consecutive leucinerich repeats and carry only a few glycosaminoglycan chains. The best charcterized members of this group are decorin and biglycan. In vivo experiments indicate a role for small proteoglycans in adhesion, multiplication, differentiation and migration of cells and they have been shown to bind growth factors, various collagens and fibronectin. In this article, decorin will be used as the model for the small proteoglycans. Biosynthesis, function and regulation of gene expression will be examined.
Verotoxins of enterohemorrhagic E. coli, the major causes of hemorrhagic colitis and hemolytic uremic syndrome, are subunit toxins. The B-subunits bind glycosphingolipids of the globoseries on cell surfaces and are thus responsible for the cellular specificity. Terminal Galα1-4Gal residue is required for verotoxin-binding. Investigations have shown that changes in the lipid moiety can affect verotoxin binding and that chemical modification can permit recognition of internal Galα1-4Gal under certain conditions, suggesting a degree of flexibility in the carbohydrate conformation. Structural studies of the verotoxins using site-directed mutagenesis, chemical modification of amino acids, and crystal structure analysis have led to the identification of several amino acids important for binding to the glycolipid receptors. Similar amino acid sequences have been found in membrane proteins of mammalian cells, suggesting that glycolipid-binding may be involved in the function of such proteins. Verotoxins may thus provide a useful probe of glycolipid function in cell physiology.