Oligosaccharide branching of glycoproteins: biosynthetic mechanisms and possible biological functions

Abstract

One of the most striking features of N - and O -glycosyl oligosaccharides and of lipid-linked oligosaccharides is the high degree of branching of these complex structures. Both proteins and nucleic acids are essentially linear structures and are synthesized by template mechanisms. The branched nature of complex carbohydrates dictates a totally different mechanism of biosynthetic control. Although there are undoubtedly many factors controlling this assembly (e.g. subcellular compartmentation, availability of substrates, cations), our laboratory has studied primarily the enzymatic factors that control the assembly of branched N -glycosyl (Asn-GlcNAc type) and O -glycosyl (Ser[Thr]-GalNAc type) oligosaccharides. There are three basic types of control points that appear to direct biosynthesis, ( a ) There may be two or more enzymes capable of acting on a single common substrate. Control at this juncture is exerted by the relative activities of these enzymes in a particular tissue. ( b ) Addition of a specific sugar to the growing oligosaccharide may shut off one or more subsequent enzyme steps, thereby ‘freezing* the structure at a certain stage in its synthesis, ( c ) Progression of the pathway may be impossible until a certain key sugar residue is inserted into the growing oligosaccharide chain. Examples of all three types of control occur in the assembly of both N - and O -glycosyl oligosaccharides. This paper discusses our work on the N -acetylglucosaminyl transferases, which initiate branches in N -glycosyl oligosaccharides, as well as some studies on glycosyltransferases that control the assembly of the four basic Ser(Thr)-GalNAc cores. Important features at all stages of control are the three-dimensional shape of the oligosaccharide, the effect of certain key sugar residues on this three-dimensional shape and the stereochemistry of the interaction of oligosaccharides with proteins. From a functional point of view, protein-oligosaccharide interaction is of vital importance not only to enzyme control mechanisms but to a variety of biological problems such as malignancy and cell-cell interactions, differentiation and development, and susceptibility of cells to hormones, drugs and toxins.