Protein Glycosylation: Implications for In Vivo Functions and Therapeutic Applications - Advances in Biochemical Engineering Biotechnology - page 173

N -glycans or SA had no effect [138].A Gal residue at the nonreducing terminus
of these O -glycans is essential for binding of sperm to the zona pellucida.
The stable cell surface expressions of human interleukin-2 receptor, low
density lipoprotein receptor and the major antigen envelope protein of Epstein-
Barr virus depend on normal O -glycosylation [139]. The O -glycans may inhibit
proteolytic degradation of proteins [28]. The role of O -glycan in the activity of
human granulocyte colony stimulating factor (G-CSF) was suggested to be eit-
her stabilization of protein conformation or inhibition of polymerization,which
would deactivate the factor [140].
Ser/Thr O- linked Gn is found primarily in the cytoplasm and in the nucleus.
The role of O -Gn as regulating modification is not completely understood.
O -Gncylation appears to be as abundant as phosphorylation, and is a highly
dynamic and a regulated process [141]. O -Gn may have a role in modulating
either the phosphorylation state or the assembly and disassembly of multimeric
protein complexes in several major cellular systems including transcription,
nuclear transport, and cytoskeletal organization [142].
4
Altered Glycosylation Pattern and Diseases
Inappropriate expression of GlycTs is reflected in the altered glycosylation
patterns that accompany viral and chemical transformations, oncogenic events
and other pathological states such as rheumatoid arthritis and cystic fibrosis.
Increase in sialylation and branching of glycan structures expressed by cancer
cells have been correlated with increase in metastatic capacity of these cells
[143]. These changes in the glycosylation profile can be exploited in the diagno-
sis, as the serum level lipid-bound sialic acid (LSA) has been found to increase
in most cases of metastasis diseases [144, 145].
Again, unregulated appearance of selectins and inappropriate extravasation
of leukocytes results in tissue damage associated with a number of inflamma-
tory diseases, such as rheumatoid arthritis, asthma, myocardial infarction, and
acute lung injury. It is important for the therapeutic control of selectin synthe-
sis. New anticancer agents could be developed based on the inhibition of adhe-
sion by neutralizing antibodies and administration of competing glycans or
peptides to block receptor-ligand interaction. The carbohydrate ligands of
E- and P-selectin have been shown to be potentially useful for this purpose
[146]. Another means to inhibit selectin activity is to identify compounds that
selectively block either the signaling pathways or the transcription factors in-
volved in induction of genes encoding the selectins [147].
The molecular basis of inherited defects is established for a number of dis-
eases and altered glycosylation patterns have been observed to be associated
with these.For example,IgG Fc fragment conserved site glycans lacking in outer
arm Gal residues increase in rheumatoid arthritis, tuberculosis and Crohn's
disease. There is also an Fab-specific increase in glycans bearing a bisecting Gn
and a core Fuc [148].