As listed in Table 46–1, glycoproteins have many different functions, including transport molecules, immunological molecules, and hormones. They are also important in fertilization and inflammation; a number of diseases are due to defects in the synthesis and catabolism of glycoproteins.

Table1. Some Functions Served by Glycoproteins

Glycoproteins Are Important in Fertilization

To reach the plasma membrane of an oocyte, a sperm has to traverse the zona pellucida (ZP), a thick, transparent, envelope that surrounds the oocyte. The glycoprotein ZP3 is an O-linked glycoprotein that functions as a sperm receptor. A protein on the sperm surface interacts with the oligosaccharide chains of ZP3. By transmembrane signaling, this interaction induces the acrosomal reaction, in which enzymes such as proteases and hyaluronidase along with other contents of the acrosome of the sperm are released. Liberation of these enzymes permits the sperm to pass through the zona pellucida and reach the plasma membrane of the oocyte. Another glycoprotein, PH-30, is important in binding of the sperm plasma membrane to that of the oocyte, and the subsequent fusion of the two membranes, enabling the sperm to enter and fertilize the oocyte.

Selectins Play Key Roles in Inflammation & in Lymphocyte Homing

Leukocytes play important roles in many inflammatory and immunological processes; the first steps are interactions between circulating leukocytes and endothelial cells prior to passage of the leukocytes out of the circulation. Leukocytes and endothelial cells contain cell surface lectins, called selectins, which participate in intercellular adhesion. Selectins are single-chain Ca2+-binding transmembrane proteins; the amino terminals contain the lectin domain, which is involved in binding to specific carbohydrate ligands.

Interactions between selectins on the neutrophil cell sur face and glycoproteins on the endothelial cell trap the neutrophils temporarily, so that they roll over the endothelial surface. During this the neutrophils are activated, undergo a change in shape, and now adhere firmly to the endothelium. This adhesion is the result of interactions between integrins on the neutrophils and immunoglobulin-related proteins on the endothelial cells. After adhesion, the neutrophils insert pseudopodia into the junctions between endothelial cells, squeeze through these junctions, cross the basement membrane, and are then free to migrate in the extravascular space.

Selectins bind sialylated and fucosylated oligosaccha rides. Sulfated lipids may also be ligands. Administration of compounds or monoclonal antibodies that block selectin-ligand interactions may be therapeutically useful to inhibit inflammatory responses. Cancer cells often have selectin ligands on their surfaces, which may have a role in the invasion and metastasis of cancer cells.

Abnormalities in the Synthesis of Glycoproteins Underlie Certain Diseases

Leukocyte adhesion deficiency II is a rare condition caused by mutations affecting the activity of a Golgi-located GDP fucose transporter. The absence of fucosylated ligands for selectins leads to a marked decrease in neutrophil rolling. Patients suffer life-threatening recurrent bacterial infections, and also psychomotor and mental retardation. The condition may respond to oral fucose.

Paroxysmal nocturnal hemoglobinuria is an acquired mild anemia characterized by the presence of hemoglobin in urine due to hemolysis of red cells, particularly during sleep, reflecting a slight drop in plasma pH during sleep, which increases susceptibility to lysis by the complement system. The condition is due to the acquisition by hematopoietic cells of somatic mutations in the gene coding for the enzyme that links glucosamine to phosphatidylinositol in the GPI structure. This leads to a deficiency of proteins that are anchored to the red cell membrane by GPI linkages. Two proteins, decay accelerating factor and CD59, normally interact with components of the complement system to prevent the hemolysis. When they are deficient, the complement system acts on the red cell membrane to cause hemolysis.

Some of the congenital muscular dystrophies are the result of defects in the synthesis of glycans in the protein α-dystroglycan. This protein protrudes from the surface mem brane of muscle cells and interacts with laminin-2 (merosin) in the basal lamina. If the glycans of α-dystroglycan are not correctly formed (as a result of mutations in genes encoding some glycosyltransferases), this results in defective interaction of α-DG with laminin.

Rheumatoid arthritis is associated with an alteration in the glycosylation of circulating immunoglobulin G (IgG) molecules (see Chapter 52), such that they lack galactose in their Fc regions and terminate in N-acetylglucosamine. Mannose binding protein, a lectin synthesized by liver cells and secreted into the circulation, binds mannose, N-acetylglucosamine, and some other sugars. It can thus bind agalactosyl IgG molecules, which subsequently activate the complement system, contributing to chronic inflammation in the synovial membranes of joints.

Mannose-binding protein can also bind sugars when they are present on the surfaces of bacteria, fungi, and viruses, preparing these pathogens for opsonization or for destruction by the complement system. This is an example of innate immunity, which does not involve immunoglobulins or T lymphocytes. Deficiency of this protein in young infants as a result of mutation renders them susceptible to recurrent infections.

Inclusion Cell (I-Cell) Disease Results From Faulty Targeting of Lysosomal Enzymes

 Mannose 6-phosphate serves to target enzymes into the lysosome. I-cell disease is a rare condition characterized by severe progressive psychomotor retardation and a variety of physical signs, with death often occurring in the first decade of life. Cells from patients with I-cell disease lack almost all of the normal lysosomal enzymes; the lysosomes thus accumulate many different types of undegraded molecules, forming inclusion bodies. The patients’ plasma contains very high activities of lysosomal enzymes, suggesting that the enzymes are synthesized but fail to reach their proper intracellular destination and are instead secreted. Lysosomal enzymes from normal individuals carry the mannose 6-phosphate recognition marker, cells from patients with I-cell disease lack the Golgi-located N-acetylglucosamine phosphotransferase. Two lectins act as mannose 6-phosphate receptor proteins; both function in the intracellular sorting of lysosomal enzymes into clathrin coated vesicles in the Golgi. These vesicles then leave the Golgi and fuse with a prelysosomal compartment.

Genetic Deficiencies of Glycoprotein Lysosomal Hydrolases Cause Diseases Such as α-Mannosidosis

Turnover of glycoproteins involves the catabolism of the oligosaccharide chains by a number of lysosomal hydrolases, including α-neuraminidase, β-galactosidase, β-hexosaminidase, α- and β-mannosidases, α-N-acetylgalactosaminidase, α-fucosidase, endo-β-N-acetylglucosaminidase, and aspartylglucosamini dase. Genetic defects of these enzymes result in abnormal degradation of glycoproteins. The accumulation in tissues of partially degraded glycoproteins leads to various dis eases. Among the best recognized of these are mannosidosis, fucosidosis, sialidosis, aspartylglucosaminuria, and Schindler disease, due respectively to deficiencies of α-mannosidase, α-fucosidase, α-neuraminidase, aspartylglucosaminidase, and α-N-acetylgalactosaminidase.

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مواضيع ذات صلة

Isoforms of Cytochrome P450 Hydroxylate a Wide Variety of Xenobiotics in Phase 1 Metabolism

Glycans are involved in The Binding of Viruses, Bacteria, & Some Parasites to Human Cells

The Biosynthesis of N-Linked Glycoproteins Involves Dolichol-P-P-Oligosaccharide

Glycoproteins Contain Several Types of O-Glycosidic Linkages

There are Three major classes of Glycoproteins

Biochemical Markers of Bone Remodeling in Postmenopausal Osteoporosis

Biochemical Markers of Bone Remodeling in Different Clinical Conditions Affecting Bone Tissue Metabolism

Free Radicals & Antioxidant Nutrients

Vitamin B12 is Found only in Foods of Animal Origin

Vitamin B6 is important in Amino Acid & Glycogen Metabolism & in Steroid Hormone Action

Niacin is not Strictly A Vitamin

Bone Tissue Biochemistry