Glycomics

Glycomics is the systematic study of protein-glycan interaction and function. Glycans are information rich molecules composed of complex carbohydrates (sugars or polysaccharides) that are often attached to proteins and lipids. Studying glycomics is not an easy task due to linkage forms(e.g., alpha1-3, beta 1-4) and branching events that increase the structural complexity of glycans. Furthermore, glycans can not be directly sequenced and synthesized like DNAs and proteins.

Glycosylation is a form of post- or co-translational modification occurring in all eukaryotic proteins. More than 50% of all known proteins are estimated to be glycosylated. Many glycans exist only for protective purposes against external physical stresses like freezing and biochemical attacks (e.g., proteases). Some glycans like the ABO blood group antigens, however, represent major histocompatibility complex antigens which have crucial roles in cell-cell recognition events.

Cell-surface glycans are taken advantage of by various microbes to achieve infection of their host cells. In fact, most bacterial toxins can be classified as AB toxins, consisting of a toxic A chain and a carbohydrate binding protein (lectin) B chain. These include cholera, diphteria, tubercular and cero toxins. Influenza virus also contains hemagglutinin (HA) lectin to enter the host cells.

Lectins or carbohydrate binding proteins serve a number of vital roles such as the following:

intracellular sorting; An example of this is lysosomal hydolases which are transported through the golgi and eventually end up in lysosomes. These hydrolases have a unique marker, Mannose-6-phosphate, which are recognized by M6P receptors in the trans-golgi.
clearance of serum proteins; sialic acids on the nonreducing end of oligosccharide chains protects those proteins from rapid degradation in the serum. Exposure of galactose after removal of sialic acid render the protein susceptible to the binding of a receptor on hepatocytes which take up the complex by endocytosis and degrade it in lysosomes. Most peptide and proteins that are injected into humans are also rapidly degraded unless carbohydrate is attached. Proteins with manose or galactose as the nonreducing terminal sugar are rapidly recognized by mannose or galactose receptors. Pharmaceutical companies like Neose are developing strategies to glycosylate proteins to improve serum half life, using chemical and enzymatic techniques.
complement cascade; Mannose binding lectins found in the serum bind 3 adjacent mannose residues on the surface of invading pathogens which helps initiate the complement cascade. Host structures do not have 3 mannose residues this close together, and are not recognized.
cell-cell interaction and inflammation; The endothelium express selectins which upon binding to their carboyhydrate containing receptors on neutrophils, initiate a rolling adhesion of neutrophils. The neutrophils in turn activate their integrins which bind to endotheilial ICAM permitting a firmer adhesion.

Companies like Glycominds have developed glycochips which allow detection of proteins or cells to particular oligosaccharide structures. These chips may prove useful for development of drugs that inhibit cell-cell interaction, such as occurs during inflammation.

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