• 1. High-mannose type contains all mannose outside the core in varying amounts.
• 2. Hybrid type contains various sugars and amino sugars.
• 3. Complex type is similar to the hybrid type, but in addition, contains sialic acids to varying degrees.

Structures of carbohydrates on the 3 major classes of glycoprotein

O-linked sugars: The synthesis of O-linked glycoproteins occurs via the stepwise addition of nucleotide-activated sugars directly onto the polypeptide. The nucleotide-activated sugars are coupled to either UDP, GDP (as with mannose) or CMP (for instance, NANA). The attachment of sugars is catalyzed by specific glycoprotein glycosyltransferases. Evidence indicates that each specific type of carbohydrate linkage in O-linked glycoproteins is the result of a different glycosyltransferase.

N-linked sugars: As indicated earlier, the three major classes of N-linked carbohydrate modifications are high-mannose, hybrid and complex. The major distinguishing feature of the complex class is the presence of sialic acid, whereas the hybrid class contains no sialic acid.

• 1. The ABO blood group antigens are the carbohydrate moieties of glycolipids on the surface of cells as well as the carbohydrate portion of serum glycoproteins. When present on the surface of cells the ABO carbohydrates are linked to sphingolipid and are therefore of the glycosphingolipid class. When the ABO carbohydrates are associated with protein in the form of glycoproteins they are found in the serum and are referred to as the secreted forms. Some individuals produce the glycoprotein forms of the ABO antigens while others do not. This property distinguishes secretors from non-secretors, a property that has forensic importance such as in cases of rape.

Structure of the ABO Blood Group Carbohydrates R represents the linkage to protein in the secreted forms, sphingolipid in the cell-surface bound form

• 2. The truncation of erythrocyte surface glycoproteins leads to cell clumping, as in HEMPAS (congenital dyserythropoietic anemia type II).

• 3. Several viruses, bacteria and parasites have exploited the presence of cell-surface carbohydrates, principally associated with protein (glycoproteins), using them as portals of entry into the cell.
  • A. Human immunodeficiency virus (HIV), the causative agent of AIDS, gains entry into cells of the immune system by attaching to a class of cellular receptors known as the chemokine receptors, most notably CXCR4 and CCR5.
  • B. Members of the poxvirus family of viruses gain entry into cells, most frequently migratory leukocytes, by attaching to chemokine receptors including CCR1, CCR5 and CXCR4 (Science [1999] vol. 286 pp. 1968-1971).
  • C. Dystroglycan (DG) is a component of the dystrophin-glycoprotein complex. It is a laminin receptor encoded by a single gene and cleaved by postranslational processing into two proteins, peripheral membrane a-DG and transmembrane b-DG. a-DG interacts with laminin-2 in the basal lamina and b-DG binds to dystrophin containing cytoskeletal proteins in muscle and peripheral nerves. DG is involved in agrin- and laminin-induced acetylcholine receptor clustering at neuromuscular junctions, morphogenesis, early development, and the pathogenesis of muscular dystrophies. Recent evidence (Science (1998) vol. 282 pp. 2076-2079 and 2079-2081) demonstrates that a-DG present on Schwann cell membranes is the receptor for Mycobacterium leprae and also serves as the receptor for the arenavirus class of pathogens. Arenaviruses cause hemorrhagic fever in humans. Lymphocytic choriomeningitis virus (LCMV), Lassa fever virus (LFV), Oliveros and Mobala (all members of the arenavirus family) all bind to a-DG. The specificity of this interaction was demonstrated by the resistance to LCMV infection of cells harboring a null mutation in DG.

  • D. Rhinoviruses utilize attachment to ICAM-1 (intercellular adhesion molecule-1) to gain entry into cells.

  • E. The pathogenic human parvovirus, B19, attaches to the erythrocyte-specific cell-surface globoside identified as erythrocyte P antigen to infect erythrocytes.

  • F. The malarial parasite Plasmodium vivax, binds to the erythrocyte chemokine receptor known as the Duffy blood group antigen (also known as the erythrocyte receptor for interleukin-8) to infect erythrocytes.

  • G. The MN blood group system is a well-characterized set of erythrocyte surface antigens that represent the variable carbohydrate modifications of the trans-membrane glycoprotein, glycophorin. Glycophorin is the cellular receptor for influenza virus as well as the receptor for erythrocyte invasion by the malarial parasite Plasmodium falciparum.

  • H. Helicobacter pylori is the bacterium responsible for chronic active gastritis and gastric and duodenal ulcers; it is also the causative agent for one of the most common forms of cancer in humans, adenocarcinoma. This bacterium attaches to the Lewis blood group antigen on the surfaces of gastric mucous cells.

  • I. Rabies virus binds to cells through interactions with neural cell adhesion molecule (N-CAM).

  • J. The receptor for fibroblast growth factor (FGF) has been reported to be the portal of entry for human herpes virus Type I. Recent new evidence indicates that the portal of entry for human herpes simplex Type I viruses is 3-O-sulfated heparan sulfate (Cell 99:13-22, 1999).

  • K. Human herpesvirus 6 (HHV-6) infection occurs in virtually all persons within the first 2 years of life and persists the entire lifetime. In immunocompromised patients HHV-6 causes opportunistic infections and is the causative agent of exanthema subitum. HHV-6 has been linked to multiple sclerosis and to the progression of AIDS. The cellular receptor for HHV-6 is the cell-surface type-I glycoprotein, CD46 (Cell 99:817-827, 1999).

• 4. Some glycoproteins are tethered to the membrane by a lipid linkage: the protein is attached to the carbohydrate through phosphatidylethanolamine (PE) linkage, and the carbohydrate is in turn attached to the membrane via linkage to phosphatidylinositol (PI), which anchors the structure within the membrane. The linkage is called a glycosylphosphotidylinositol (GPI) anchor, and proteins that are anchored in this way are termed glypiated proteins. The disease, paroxysmal nocturnal hemoglobinuria, results from the loss of the erythrocyte surface glycoprotein, decay-accelerating factor, (DAF). DAF prevents erythrocyte lysis by complement. When this factor is lost from the erythrocyte surface, abnormal hemolysis occurs, with the end result of hemoglobin accumulation in the urine.

• 5. The proper degradation of glycoproteins has medical relevance. Degradation occurs within lysosomes and requires specific lysosomal hydrolases, termed glycosidases. Exoglycosidases remove sugars sequentially from the non-reducing end and exhibit restricted substrate specificities. In contrast, endoglycosidases cleave carbohydrate linkages from within and exhibit broader substrate specificities. Several inherited disorders involving the abnormal storage of glycoprotein degradation products have been identified in humans. These disorders result from defects in the genes encoding specific glycosidases, leading to incomplete degradation and subsequent over-accumulation of partially degraded glycoproteins. As a general class, such disorders are known as lysosomal storage diseases and include the diseases known as mucolipidoses that result from incomplete degradation of the carbohydrate portions of glycolipids.

• 6. Defects in the proper targeting of glycoproteins to the lysosomes can also lead to clinical complications. Deficiencies in the enzyme responsible for the transfer of GlcNAc-1-P to Man residues (GlcNAc phosphotransferase) in lysosomal enzymes leads to the formation of dense inclusion bodies formation in the fibroblasts. Two disorders related to deficiencies in the targeting of lysosomal enzymes are termed I-cell disease (mucolipidosis II) and pseudo-Hurler polydystrophy (mucolipidosis III, also called mucolipidosis-HI). I-cell disease is characterized by severe psychomotor retardation, skeletal abnormalities, coarse facial features, painful restricted joint movement, and early mortality. Pseudo-Hurler polydystrophy is less severe; it progresses more slowly, and afflicted individuals live to adulthood.