Harpers

GLYCOPROTEINS / 533Table 47–17. Major features of some diseases(eg, α-mannosidosis, β-mannosidosis, fucosidosis,sialidosis, aspartylglycosaminuria, and Schindlerdisease) due to deficiencies of glycoproteinhydrolases. 1• Usually exhibit mental retardation or other neurologic abnormalities,and in some disorders coarse features or visceromegaly(or both)• Variations in severity from mild to rapidly progressive• Autosomal recessive inheritance• May show ethnic distribution (eg, aspartylglycosaminuria iscommon in Finland)• Vacuolization of cells observed by microscopy in somedisorders• Presence of abnormal degradation products (eg, oligosaccharidesthat accumulate because of the enzymedeficiency) in urine, detectable by TLC and characterizableby GLC-MS• Definitive diagnosis made by assay of appropriate enzyme,often using leukocytes• Possibility of prenatal diagnosis by appropriate enzymeassays• No definitive treatment at present1 MIM numbers: α-mannosidosis, 248500; β-mannosidosis,248510; fucosidosis, 230000; sialidosis, 256550; aspartylglycosaminuria,208400; Schindler disease, 104170.tem reflects the importance of glycoproteins in the developmentand normal function of that system.From the above, it should be apparent that glycoproteinsare involved in a wide variety of biologicprocesses and diseases. Glycoproteins play direct or indirectroles in a number of other diseases, as shown inthe following examples.(1) The influenza virus possesses a neuraminidasethat plays a key role in elution of newly synthesizedprogeny from infected cells. If this process is inhibited,spread of the virus is markedly diminished. Inhibitorsof this enzyme are now available for use in treating patientswith influenza.(2) HIV-1, thought by many to be the causativeagent of AIDS, attaches to cells via one of its surfaceglycoproteins, gp120.(3) Rheumatoid arthritis is associated with an alterationin the glycosylation of circulating immunoglobulin-γ(IgG) molecules (Chapter 50), suchthat they lack galactose in their Fc regions and terminatein GlcNAc. Mannose-binding protein (not to beconfused with the mannose-6-P receptor), a C-lectinsynthesized by liver cells and secreted into the circulation,binds mannose, GlcNAc, and certain other sugars.It can thus bind the agalactosyl IgG molecules, whichsubsequently activate the complement system, contributingto chronic inflammation in the synovial membranesof joints. This protein can also bind the abovesugars when they are present on the surfaces of certainbacteria, fungi, and viruses, preparing these pathogensfor opsonization or for destruction by the complementsystem. This is an example of innate immunity, not involvingimmunoglobulins. Deficiency of this protein inyoung infants, due to mutation, renders them very susceptibleto recurrent infections.Other disorders in which glycoproteins have beenimplicated include hepatitis B and C, Creutzfeldt-Jakob disease, and diarrheas due to a number of bacterialenterotoxins. It is hoped that basic studies of glycoproteinsand other glycoconjugates (ie, the field ofglycobiology) will lead to effective treatments for diseasesin which these molecules are involved. Already, atleast two disorders have been found to respond to oralsupplements of sugars.The fantastic progress made in relation to thehuman genome has stimulated intense interest in bothgenomics and proteomics. It is anticipated that the paceof research in glycomics—characterization of the entirecomplement of sugar chains found in cells (the glycome)—willalso accelerate markedly. For a number ofreasons, this field will prove more challenging than eithergenomics or proteomics. These reasons include thecomplexity of the structures of oligosaccharide chainsdue to linkage variations—in contrast to the generallyuniform nature of the linkages between nucleotides andbetween amino acids. There are also significant variationsin oligosaccharide structures among cells and atdifferent stages of development. In addition, no simpletechnique exists for amplifying oligosaccharides, comparableto the PCR reaction. Despite these and otherproblems, it seems certain that research in this area willuncover many new important biologic interactions thatare sugar-dependent and will provide targets for drugand other therapies.SUMMARY• Glycoproteins are widely distributed proteins—withdiverse functions—that contain one or more covalentlylinked carbohydrate chains.• The carbohydrate components of a glycoproteinrange from 1% to more than 85% of its weight andmay be simple or very complex in structure.• At least certain of the oligosaccharide chains of glycoproteinsencode biologic information; they are alsoimportant to glycoproteins in modulating their solubilityand viscosity, in protecting them against proteolysis,and in their biologic actions.