Chemistry Reference
In-Depth Information
proteins in the cytosol thereby disrupting their normal functions including regula-
tion of the epithelial cell barrier [7] .
C. diffi cile
is an opportunistic pathogen and the
most common cause of antibiotic-associated diarrhea. Antibiotics disturb the normal
bacterial fl ora of the intestine, allowing for
C. diffi cile
overgrowth.
17.1.3.2
Cholera Toxin
Vibrio cholerae
colonizes the small intestine and cause diarrhea by secretion of a
toxin (CT) that disrupts the epithelial cell barrier of the small intestine. CT consists
of two subunits. The A subunit exerts the toxic effect of CT, while the B subunits
are responsible for its carbohydrate-binding activity. There are fi ve B subunits per
toxin, assembled into a pentameric ring, each of them capable of binding with high
affi nity to a GM1 (see Chapter 25.2 and Info Box 1 in Chapter 30 for the function
of GM1 in growth control of human tumor cells and Figure 30.2 for structure)
molecule. Studies indicate that this binding takes place at GM1- containing lipid
rafts. As GM1 recycles between the cell surface and the Golgi, this may be the
toxin's way into the cells [8].
17.1.3.3
Heat - Labile and Heat - Stable Toxins
Enterotoxigenic
E. coli
produce heat-labile toxin (LT). It is closely related and very
similar to CT both in structure and binding [9]. It too is built up by one A subunit
(toxic effect) and fi ve B subunits (lectin activity) that bind to the GM1 glycosphin-
golipids (for further information on GM1, please see Chapter 10.7 - 10.10 and Info
Box 1 in Chapter 30). However, slight differences do exist as shown by the fact
that LT can bind also to desialylated and/or degalactosylated GM1. It also recog-
nizes GM2 and paragloboside which CT does not.
Another toxin produced by enterotoxigenic
E. coli
is heat - stable toxin ( ST ) [9] .
The ligand for this toxin is believed to be
1,2 - fucosylated structures (H type 1
and H type 2) as indicated by studies showing that milk oligosaccharides carrying
these carbohydrate epitopes protect infants against ST. Enterotoxigenic
E. coli
in
contaminated water and food is a common cause of diarrhea in humans as well
as pigs. Individuals at high risk for enterotoxigenic
E. coli
infection are travelers,
children below the age of 5 years and infants fed milk substitutes. Although
related, LT and ST have different mechanisms of action on intestinal epithelial
cells. When coexpressed by enterotoxigenic
E. coli
strains, they act synergistically
to cause diarrhea.
α
17.1.3.4
Shiga and Shiga
-
Like Toxins
Similar to CT, the shiga and shiga- like toxins [10, 11] consist of a toxic A subunit
and fi ve carbohydrate-binding B subunits. Shiga toxin is produced by
Shigella dys-
enteriae.
The toxin binds to Gb3-expressing cells and, upon internalization, inhibits
protein synthesis leading to diarrhea, hemorrhagic colitis or hemolytic uremic
syndrome in infected individuals (for structure of the globo-series triaose, please
see also Tables 10.2 and 10.5). It has been shown that cytokines induced by
S. dysenteriae
infection can cause production of Gb3 in some cells. Shiga- like toxin 1
is nearly identical with shiga toxin and also recognizes Gb3. Shiga-like toxin 2
exists in different forms; most of them also recognize Gb3, but one form has been
