How are glycoprotein sugar chains functioning within us?

 Glycoproteins are complexes in which carbohydrates are attached covalently to asparagine (N-glycans) or serine/threonine (O-glycans) residues of peptides (Fig. 1). Most proteins synthesized in mammalian cells are glycosylated. The N- and O-glycans contain different core structures but biologically active oligosaccharides are often found on outer chains attached to these cores. In addition, glycoproteins with N-acetylglucosaminylated or mannosylated serine/threonine residues are found in various cellular compartments and tissues. Attachment of oligosaccharides to peptides will increase solubility, cover the antigenic domains and protect peptide backbone against proteases. Like polysialic acid attached to neural cell adhesion molecules (N-CAM), the carbohydrates often modulate protein functions. In contrast, the carbohydrate moieties of serum glycoproteins and pituitary glycoprotein hormones are involved in their clearance from circulation or targeting of the hormones to respective organs. N-glycosylation occurs in most animal species, but species- or organ-specific carbohydrates are present. Therefore, it is important to evaluate the carbohydrate structures of recombinant products when they are applied to humans since we have strong natural antibodies against the carbohydrates. In lower animals carbohydrate structures and glycosyltransferase activities which are usually not found in higher organisms have been described. These findings provide bases for evaluating why individual animals acquired or required respective carbohydrate structures.
Fig. 1Figure
The best known role of the carbohydrates is that the carbohydrate is one of the complementary molecules recognized by the protein family, "selectin", expressed on endothelial cells or lymphocytes when leukocytes migrate into the sites of inflammation or when mature lymphocytes migrate from or to the blood circulation to or from the lymphatic circulation. During development of mouse embryo a dramatic change in the expression pattern of cell surface antigens, which are mainly carbohydrates, is observed. Treatment of embryos with haptenic sugars or biosynthetic inhibitors of glycosyltransferases or processing glycosidases resulted the arrest of development at certain stages, suggesting that the carbohydrate antigens are essential for embryogenesis probably by the involvement of specific cellular interactions. In support of this, the presence of a lectin-like molecule has been demonstrated in frog cleavage cells. Altered glycosylation of cell surface glycoproteins has been observed for tumor cells, and is involved in the metastatic processes. Disadvantages of the expressed carbohydrates at cell surface are that cells lining the trachea, stomach and intestines open a way for microorganisms and viruses to invade the cells. Thus, the carbohydrates are really a gateway for foreign organisms and tumor cells but at the same time they are the door for aggregation of single cells from which multicellular organisms are born. It has been well documented that accumulation of oligosaccharides in lysosomes due to defects in lysosomal hydrolases causes serious diseases in humans. Recently diseases which arise from a deficiency in biosynthetic enzymes of the carbohydrates have been described. Patients who develop multiple symptoms by neuropathy have been shown to contain underglycosylated serum glycoproteins, and the disease appears to originate from defective N-glycosylation, which is termed the carbohydrate-deficient glycoprotein syndrome (CDGS). Other patients with congenital dyserythropoietic anemia (CDA type II) have abnormal red blood cells whose altered morphology could be caused by the truncation of N-glycans arising from a deficiency either in N-acetylglucosaminyltransferase (GlcNAcT)-II or alpha-mannosidase II which is involved in the processing of N-glycans. These results strongly indicate that carbohydrates are important for our health.

The enzyme, GlcNAcT-I, is key to the formation of complex-type and hybrid-type sugar chains. Complex-type sugar chains consist of two to five GlcNAc outer chains which are, in many cases, extend with beta-1,4-linked galactose and terminated with alpha-2,6-linked sialic acid. Targeted inactivation of the mouse GlcNAcT-I gene has been shown to result in death of mice at mid-embryonic stages, whereas ablation of the beta-1,4-galactosyltransferase (beta-1,4-GalT I) gene resulted in growth retardation and early death of the mice. In contrast, inactivation of alpha-2,6-sialyltransferase (ST6-Gal I) in gene-targeted mice showed no impaired development, growth and differentiation except for a decrease in a B-lymphocyte population in peripheral blood and spleen. These results indicate that the respective sugar moieties are indispensable for embryogenesis (Fig. 2). However, there is no knowledge available about how mutation leads to the lethal or semi-lethal fate of these mice since defects of carbohydrates affect most proteins.

In this series, current knowledge of carbohydrates functioning in individual glycoproteins, cells or tissues will be provided. The more dynamic functional aspects of the carbohydrates will be brought about by further analyses of mice with loss-of-function or gain-of-function generated by manipulation of single or multiple glycogenes in the near future.
Fig. 2Figure
Kiyoshi Furukawa (Department of Biosignal Research, Tokyo Metropolitan Institute of Gerontology )
Reference(1) Bhavanadan, VP, Furukawa, K : Biochemistry and oncology of sialoglycoproteins in "Biology of the Sialic Acids" (Rosenberg, A., ed.), pp.145-196, Plenum Press, New York, 1995.
Jun.15, 1998

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