Glycoproteins and Their Relationship to Human Disease

Abstract

Glycoproteins are proteins that carry N- and O-glycosidically-linked carbohydrate chains of complex structures and functions. N-glycan chains are assembled in the endoplasmic reticulum and the Golgi by a controlled sequence of glycosyltransferase and glycosidase processing reactions involving dolichol intermediates. The assembly of O-glycans occurs in the Golgi and does not involve dolichol. For most reactions, families of glycosyltransferases exist; the expression of the individual enzymes within a family is often subject to complex regulation. The biosynthesis of N- and O-glycan is controlled at the level of gene expression, mRNA, enzyme protein activity and localization, and through substrate and cofactor concentrations at the site of synthesis. This complex regulation results in many hundreds of structures, the range of which varies in different species, cell types, tissue types, states of development and differentiation. In diseased cells, the relative proportions of these structures are often characteristically different from normal, and may be useful for the assessment of the stage of the disease and for diagnosis. Knowledge of disease-specific glycoprotein structures and their functions may be used therapeutically, in immunotherapy, in blocking cell adhesion or interfering with other binding or biological processes. Recently, some of the mechanisms underlying glycoprotein alterations in disease have been elucidated. This opens the possibility of an active interference in the disease process. The functions of glycans in diseased cells will become more clear with the tools of molecular biology and transgenic animal models.

New Aspects of Siglec Binding Specificities, Including the Significance of Fucosylation and of the Sialyl-Tn Epitope

“…Indeed, sialyl-Tn can be used as a diagnostic marker in many cancers (39,40), where high expression of sialyl-Tn is associated with poor prognosis (39,(41)(42)(43). The mechanism underlying the expression of this antigen on cancer cells may be a lack of expression of the glycosyltransferases that normally extend the O-glycan chains or the premature hypersialylation of the O-linked GalNAc residue, preventing the action of these extension glycosyltransferases (39,70). De-O-acetylation may be another means to generate sialyl-Tn in cancers: in normal healthy colon sialyl-Tn is found in the O-acetylated form, whereas in colonic tumors the O-acetylated form is ab- sent (71)(72)(73).…”

“…For example, since sialyl-Tn was noted as a ligand for siglec-6, the direct recognition of the sialyl-Tn epitope has never been examined for other siglecs. Sialyl-Tn is a disaccharide found frequently on a variety of cancers and is known to be a useful diagnostic marker (39,40). High expression of this antigen is associated with a poor prognosis in most cancers studied (39,(41)(42)(43).…”

Cutting Edge: Granzyme B Proteolysis of a Neuronal Glutamate Receptor Generates an Autoantigen and Is Modulated by Glycosylation

“…Modifications in glycosylation have been noted to occur during inflammation (23)(24)(25); however, in the case of GluR3B, absence of the entire glycosylation tree appears to be required for GB cleavage, suggesting that inefficiency of glycosylation at this site is responsible for GB recognition. Both inflammation (especially viral infection) and trauma have long been viewed as candidates for initiating RE pathology, in part due to the close association with the onset of encephalitis, microglial nodules consisting of activated T cell infiltrates (26), and the subsequent appearance of clinical symptoms.…”

The Relative Activities of the C2GnT1 and ST3Gal-I Glycosyltransferases Determine O-Glycan Structure and Expression of a Tumor-associated Epitope on MUC1

“…Moreover, the level of expression of the mRNA coding for ST3Gal-I correlates with the level of expression of the SM3 epitope and with tumor grade (19). Since core 2 branching by ␤6GlcNAc-transferases is inhibited by ␣2,3 sialylation of core 1 in vitro (25,26,27), it follows that ST3Gal-I could be a key controlling enzyme leading to simple mucin type core 1 glycosylation pattern in cancer cells. The question, however, is whether ST3Gal-I can effectively compete with C2GnT1 in vivo, leading to an inhibition in the formation of core 2 structures on MUC1 and whether this relates to exposure of the cancer-associated SM3 epitope.…”