Helicobacter Pylori Structure

W-Acetylneuraminic acid (Neu5Ac) (a sialic acid)

A similar mechanism is apparently responsible for removing old erythrocytes from the mammalian bloodstream. Newly synthesized erythrocytes have several membrane glycoproteins with oligosaccharide chains that end in Neu5Ac. When the sialic acid residues are removed by withdrawing a sample of blood, treating it with siali-dase in vitro, and reintroducing it into the circulation, the treated erythrocytes disappear from the bloodstream within a few hours; those with intact oligosaccharides (erythrocytes withdrawn and reintroduced without siali-dase treatment) continue to circulate for days.

Several animal viruses, including the influenza virus, attach to their host cells through interactions with oligosaccharides displayed on the host cell surface. The lectin of the influenza virus, the HA protein, is essential for viral entry and infection (see Fig. 11-25). After initial binding of the virus to a sialic acid-containing oligosac-charide on the host surface, a viral sialidase removes the terminal sialic acid residue, triggering the entry of the virus into the cell. Inhibitors of this enzyme are used clinically in the treatment of influenza. Lectins on the surface of the herpes simplex viruses HS-1 and HS-2 (the causative agents of oral and genital herpes, respectively) bind specifically to heparan sulfate on the cell surface as a first step in their infection cycle; infection requires precisely the right pattern of sulfation on this polymer.

Selectins are a family of plasma membrane lectins that mediate cell-cell recognition and adhesion in a wide range of cellular processes. One such process is the movement of immune cells (T lymphocytes) through the capillary wall, from blood to tissues, at sites of infection or inflammation (Fig. 7-33). At an infection site, P-selectin on the surface of capillary endothelial cells interacts with a specific oligosaccharide of the glycoproteins of circu

Glycoprotein ligand for integrin

Integrin

P-selectin

Glycoprotein ligand for P-selectin

Capillary endothelial cell

Glycoprotein ligand for integrin

Glycoprotein ligand for P-selectin

P-selectin

Capillary endothelial cell

Site of inflammation

Lectin Ligand Interaction

FIGURE 7-33 Role of lectin-ligand interactions in lymphocyte movement to the site of an infection or injury. A T lymphocyte circulating through a capillary is slowed by transient interactions between P-selectin molecules in the plasma membrane of the capillary endothelial cells and glycoprotein ligands for P-selectin on the T-cell surface. As it interacts with successive P-selectin molecules, the T cell rolls along the capillary surface. Near a site of inflammation, stronger interactions between integrin in the capillary surface and its ligand in the T-cell surface lead to tight adhesion. The T cell stops rolling and, under the influence of signals sent out from the site of inflammation, begins extravasation—escape through the capillary wall—as it moves toward the site of inflammation.

Site of inflammation

FIGURE 7-33 Role of lectin-ligand interactions in lymphocyte movement to the site of an infection or injury. A T lymphocyte circulating through a capillary is slowed by transient interactions between P-selectin molecules in the plasma membrane of the capillary endothelial cells and glycoprotein ligands for P-selectin on the T-cell surface. As it interacts with successive P-selectin molecules, the T cell rolls along the capillary surface. Near a site of inflammation, stronger interactions between integrin in the capillary surface and its ligand in the T-cell surface lead to tight adhesion. The T cell stops rolling and, under the influence of signals sent out from the site of inflammation, begins extravasation—escape through the capillary wall—as it moves toward the site of inflammation.

lating T cells. This interaction slows the T cells as they adhere to and roll along the endothelial lining of the capillaries. A second interaction, between integrin molecules (see p. XXX) in the T-cell plasma membrane and an adhesion protein on the endothelial cell surface, now stops the T cell and allows it to move through the capillary wall into the infected tissues to initiate the immune attack. Two other selectins participate in this "lymphocyte homing": E-selectin on the endothelial cell and L-selectin on the T cell bind their cognate oligosaccharides on the T cell and endothelial cell, respectively.

Some microbial pathogens have lectins that mediate bacterial adhesion to host cells or toxin entry into cells. The bacterium believed responsible for most gastric ulcers, Helicobacter pylori, adheres to the inner surface of the stomach by interactions between bacterial membrane lectins and specific oligosaccharides of membrane glycoproteins of the gastric epithelial cells

264 Part I Structure and Catalysis

Sulfated Gastric Glycoprotein
FIGURE 7-34 An ulcer in the making. Helicobacter pylori cells adhering to the gastric surface. This bacterium causes ulcers by interactions between a bacterial surface lectin and the Leb oligosaccharide (a blood group antigen) of the gastric epithelium.

(Fig. 7-34). Among the binding sites recognized by H. pylori is the oligosaccharide Leb when it is part of the type O blood group determinant. This observation helps to explain the severalfold greater incidence of gastric ulcers in people of blood type O than in those of type A or B. Chemically synthesized analogs of the Leb oligosaccharide may prove useful in treating this type of ulcer. Administered orally, they could prevent bacterial adhesion (and thus infection) by competing with the gastric glycoproteins for binding to the bacterial lectin.

The cholera toxin molecule (produced by Vibrio cholerae) triggers diarrhea after entering intestinal cells responsible for water absorption from the intestine. The toxin attaches to its target cell through the oligosac-charide of ganglioside GM1, a membrane phospholipid (for the structure of GM1 see Box 10-2, Fig. 1), on the surface of intestinal epithelial cells. Similarly, the pertussis toxin produced by Bordetella 'pertussis, the bacterium that causes whooping cough, enters target cells only after interacting with an oligosaccharide (or perhaps several oligosaccharides) with a terminal sialic acid residue. Understanding the details of the oligosaccharide-binding sites of these toxins (lectins) may allow the development of genetically engineered toxin analogs for use in vaccines. Toxin analogs engineered to lack the carbohydrate binding site would be harmless because they could not bind to and enter cells, but they might elicit an immune response that would protect the recipient if later exposed to the natural toxin. It is also possible to imagine drugs that would act by mimicking the oligosaccharides of the cell surface, binding to the lectins of bacteria or toxins and preventing their productive binding to cell surfaces. ■

Lectins also act intracellularly. An oligosaccharide containing mannose 6-phosphate marks newly synthe sized proteins in the Golgi complex for transfer to the lyso-some (see Fig. 27-36). A common structural feature on the surface of these glycoproteins, the signal patch, causes them to be recognized by an enzyme that phosphorylates a mannose residue at the terminus of an oligosaccharide chain. This mannose phosphate residue is recognized by the cation-dependent mannose 6-phosphate receptor, a membrane-associated lectin with its mannose phosphate binding site on the lumenal side of the Golgi complex. When a section of the Golgi complex containing this receptor buds off to form a transport vesicle, proteins containing mannose phosphate residues are dragged into the forming bud by interaction of their mannose phosphates with the receptor; the vesicle then moves to and fuses with a lysosome, depositing its cargo therein. Many, perhaps all, of the degradative enzymes (hydrolases) of the lysosome are targeted and delivered by this mechanism.

Essentials of Human Physiology

Essentials of Human Physiology

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