Harpers

Glycoproteins 47Robert K. Murray, MD, PhDBIOMEDICAL IMPORTANCEGlycoproteins are proteins that contain oligosaccharide(glycan) chains covalently attached to theirpolypeptide backbones. They are one class of glycoconjugateor complex carbohydrates—equivalent termsused to denote molecules containing one or more carbohydratechains covalently linked to protein (to formglycoproteins or proteoglycans) or lipid (to form glycolipids).(Proteoglycans are discussed in Chapter 48 andglycolipids in Chapter 14). Almost all the plasma proteinsof humans—except albumin—are glycoproteins.Many proteins of cellular membranes (Chapter 41)contain substantial amounts of carbohydrate. A numberof the blood group substances are glycoproteins,whereas others are glycosphingolipids. Certain hormones(eg, chorionic gonadotropin) are glycoproteins.A major problem in cancer is metastasis, the phenomenonwhereby cancer cells leave their tissue of origin (eg,the breast), migrate through the bloodstream to somedistant site in the body (eg, the brain), and grow therein an unregulated manner, with catastrophic results forthe affected individual. Many cancer researchers thinkthat alterations in the structures of glycoproteins andother glycoconjugates on the surfaces of cancer cells areimportant in the phenomenon of metastasis.GLYCOPROTEINS OCCUR WIDELY& PERFORM NUMEROUS FUNCTIONSGlycoproteins occur in most organisms, from bacteriato humans. Many viruses also contain glycoproteins,some of which have been much investigated, in part becausethey are very suitable for biosynthetic studies.Numerous proteins with diverse functions are glycoproteins(Table 47–1); their carbohydrate content rangesfrom 1% to over 85% by weight.Many studies have been conducted in an attempt todefine the precise roles oligosaccharide chains play inthe functions of glycoproteins. Table 47–2 summarizesresults from such studies. Some of the functions listedare firmly established; others are still under investigation.OLIGOSACCHARIDE CHAINS ENCODEBIOLOGIC INFORMATIONAn enormous number of glycosidic linkages can be generatedbetween sugars. For example, three different hexosesmay be linked to each other to form over 1000 differenttrisaccharides. The conformations of the sugars inoligosaccharide chains vary depending on their linkagesand proximity to other molecules with which the oligosaccharidesmay interact. It is now established that certainoligosaccharide chains encode considerable biologic informationand that this depends upon their constituentsugars, their sequences, and their linkages. For instance,mannose 6-phosphate residues target newly synthesizedlysosomal enzymes to that organelle (see below).TECHNIQUES ARE AVAILABLEFOR DETECTION, PURIFICATION,& STRUCTURAL ANALYSISOF GLYCOPROTEINSA variety of methods used in the detection, purification,and structural analysis of glycoproteins are listedin Table 47–3. The conventional methods used to purifyproteins and enzymes are also applicable to the purificationof glycoproteins. Once a glycoprotein hasbeen purified, the use of mass spectrometry and highresolutionNMR spectroscopy can often identify thestructures of its glycan chains. Analysis of glycoproteinscan be complicated by the fact that they often exist asglycoforms; these are proteins with identical aminoacid sequences but somewhat different oligosaccharidecompositions. Although linkage details are not stressedin this chapter, it is critical to appreciate that the precisenatures of the linkages between the sugars of glycoproteinsare of fundamental importance in determining thestructures and functions of these molecules.514