The INDIVIDUALIST

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Glycomics

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One of the primary constituents of mucin are the sialic acids (neuraminic acids), compounds responsible for many of the characteristics of mucus. The sialic acid content of mucus determines how good a lubricant the mucus will be. Mucus with a high sialic acid content retains more water and "plumps," giving it the necessary three dimensional shape needed for its job. This occurs due to charge repulsion between negatively charged residues on adjacent oligosaccharide chains. Interestingly, in the presence of small amounts of calcium the viscosity of tracheal mucus has been shown to increase rapidly. Newborn mucin seems to contain more sialic acid and less fucose than that of adult. This seems to be an integral part of the defense mechanism of the newborn. Newborn mucus also was found to bind cholera toxin much more effectively than adult mucus, perhaps explaining the decreased susceptibility of newborns to cholera. Studies using neuramidase-treated blood group antigens showed that removal of the sialic acid residue from the blood group antigens was significant only for M or N antigens, which produced a loss of allergenicity. Other blood group antigens are probably oriented by membrane sialic acids, but their loss results in no significant loss of antigenicity.

Lining the surface of most human cells, sialic acid increases the affinity of Alternate Complement Pathway enzyme C3 for its control factor ("substance H"). Thus cells which contain high amounts of sialic acid can quench the complement cascade, whereas cells without sialic acid promote it. Most bacteria and plant cells lack sialic acid, which explains why the alternative complement pathway is so important for natural resistance: the body designed complement to be inactivated by a chemical common to all "self" tissue and uncommon to all "non-self" tissue.

Sialic acids exhibit profound antimicrobial effects: many naturally occurring glycoproteins, including ovomucoids, ovalbumins, and submaxilliary mucins, inhibit the replication of rotaviruses. The inhibition has been shown to be the result of direct virus-glycoprotein binding that is largely dependent upon the interactions with sialic acid oligosaccharides. It has also been recently reported that gay men who were double recessive for the gene producing a "long" form of membrane sialic acid showed a lower incidence of conversion to clinical AIDS.

The number of negatively charged terminal sialic acid residues attached to complementary groupings on the virus surface appears to determine primarily the inhibitory potency of the glycoproteins. This was extensively studied in influenza virus systems.

Thus:

virus + glycoprotein ---- virus-glycoprotein complex.

In which the equilibrium constant as to the reversibility of the adherence of the virus to the glycoprotein complex was directly relational to both the sialic acid concentration of the glycoprotein employed, and the complementarity of the glycoprotein to the viral receptor. Several glycoproteins, including N-acetylgalactosamine can actually interfere with the access of influenza virus to binding sites on the mucous glycoprotein.

Discussion

It is interesting to speculate on the significance of increased sialotransferase activity in chronic myleogenous leukemia granulocytes (2.8 times higher in Chronic Myelogenous Leukemia (CML) cells as compared to normal cells), which may account for the aberrant sialylation of o-linked oligosaccharides in CML cell lines. CML is characterized by the inappropriate early release of immature granulocyte precursors from the bone marrow, which may indeed result from aberrant sialylation and for the-prolonged circulation time.

Sialic acid may play a role in tumor metastasis: desialylated SKNMC neuroblastoma cells had significantly diminished platelet activating activity. Many human carcinomas contain elevated levels of membrane glycoproteins and glycosyltransferase. Sialic acid and the attaching enzyme sialyltransferase probably have direct roles in tumor cell growth. Several authors have found a correlation between the spontaneous metastatic behavior of murine tumor cell lines, their surface sialylation, and the platelet-aggregating activity of their cell surface extracts. This may in part explain some of the anti-tumor effects seen with anti-thrombogenic in tumor cell metabolism, particularly coumarin.

Sialic acid-rich glycoproteins have also been shown to be involved in the adherence of proteins from several strains of E. Coli. Furthermore, sialoglycoproteins on the RBC's seem to be receptors for Plasmodium falciparum merozoites.

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