Protein synthesis, Inhibition diphtheria toxin

Figure 12.4 Inhibition of protein synthesis by diphtheria toxin transfer of an ADP-ribose moiety from NAD+ to a diphthamide residue in the elongation factor EF-2.

Many of the differences between translation in prokaryotes and eukaryotes can be seen in the response to inhibitors of protein synthesis and to toxins. The antibiotic chloramphenicol (a trade name is Ghloromycetin) binds to the A site and inhibits peptidyl transferase activity in prokaryotes, but not in eukaryotes. This property has made chloramphenicol useful in treating bacterial infections. In eukaryotes, diphtheria toxin is a protein that interferes with protein synthesis by decreasing the activity of the eukaryotic elongation factor eEF2. 

A different kind of enzyme, translocase [80700-39-6], which transfers a fragment of NAD to the protein—synthesis factor (elongation factor 2), is catalyzed by diphtheria toxin, thereby inhibiting protein synthesis (43). In tumor cells, the rate of protein synthesis is 100 to 1000 times more sensitive to diphtheria toxin than the analogous process in normal cells (41) therefore, diphtheria toxin is selectively toxic to tumor cells. 

Diphtheria toxin, Pseudomonas exotoxin A Elongation factor 2 ADP-ribosylation Inhibition of protein synthesis (diphtheria, Pseudomonas infection)... 

Diphtheria toxin, an exotoxin of Corynebacterium diphtheriae infected with a specific lysogenic phage, catalyzes the ADP-ribosylation of EF-2 on the unique amino acid diphthamide in mammalian cells. This modification inactivates EF-2 and thereby specifically inhibits mammalian protein synthesis. Many animals (eg, mice) are resistant to diphtheria toxin. This resistance is due to inability of diphtheria toxin to cross the cell membrane rather than to insensitivity of mouse EF-2 to diphtheria toxin-catalyzed ADP-ribosylation by NAD. 

Denileukin diftitox is a combination of the active sections of interleukin 2 and diphtheria toxin. It binds to high-affinity interleukin 2 receptors on the cancer cell (and other cells), and the toxin portion of the molecule inhibits protein synthesis to result in cell death. The pharmacokinetics of denileukin diftitox are best described by a two-compartment model, with an a half-life of 2 to 5 minutes and a terminal half-life of 70 to 80 minutes. Denileukin diftitox is used for the treatment of persistent or recurrent cutaneous T-cell lymphoma whose cells express the CD25 receptor. Side effects include vascular leak syndrome, fevers/chills, hypersensitivity reactions, hypotension, anorexia, diarrhea, and nausea and vomiting. 

Honjo, J., Nishizuka, Y., Hayaishi, O., and Kato, I. (1968) Diphtheria toxin-dependent adenosine diphosphate ribosylation of aminoacyl transferase II and inhibition of protein synthesis. J. Biol. Cbem. 243, 3553-3555. 

The IL-2 portion of the fusion protein facilitates product interaction with cells displaying cell surface IL-2 receptors, found in high levels on some leukaemia and lymphoma cells, including CTCL cells. Binding appears to trigger internalization of the receptor-fusion protein complex (Figure 9.B1). Sufficient quantities of the latter escape immediate cellular destruction to allow diphtheria toxin-mediated inhibition of cellular protein synthesis. Cell death usually results within hours. 

Highly potent bacterial toxins such as ricin and diphtheria can completely inhibit cellular protein synthesis at very low levels [26]. The bacterial toxin exerts cytotoxicity through enzymatic inactivation of factors essential for protein synthesis (e.g., riboso-mal RNA, elongation factor 2 or EF2). Inactivation of these proteins, which are... 

Denileukin Diftitox. Denileukin Diftitox (Ontak) is formulated by combining interleukin-2 with diphtheria toxin.11 Certain leukemia and lymphoma cells have a surface receptor that has a high affinity for interleukin-2, thus attracting this drug directly to these cells. Upon binding with tbe receptor, the diphtheria toxin component of the drug inhibits cellular protein synthesis, which ultimately results in cell death. This... 

Diphtheria Toxin Blocks Protein Synthesis in Eukaryotes by Inhibiting Translocation... 

DenUeukin diftitox is a fusion protein formed by binding human aldesleukin to the cytotoxic A chain of diphtheria toxin. This product binds to the aldesleukin receptor and inhibits protein synthesis, resulting in cell death. It has been approved for treatment of persistent or recurrent cutaneous T cell lymphoma and is being evaluated in patients with severe psoriasis. 

Diphtheria toxin inactivates elongation factor 2, an enzyme required for protein synthesis (Pappenheimer, 1977) through catalyzing its ADP-ribosylation, thereby inhibiting protein synthesis and inducing cell death. Elongation factor 2 contains a unique amino acid, diph-thamide, which is formed by posttranslational modification of a histidine residue (Van Ness et ai, 1980). The ADP-ribose binds covalently to this unusual amino acid. 

Denileukin diftitox is a fusion protein that combines portions of the IL-2 molecule with the diphtheria toxin to destroy cells with the IL-2 receptor by inhibition of protein synthesis. It is used primarily in cutaneous T-cell lymphoma (CTCL) in patients whose disease expresses the CD 25 component of the IL-2 receptor. Its major toxicity is hypersensitivity reactions and the vascular leak syndrome. 

Myelinating cells are susceptible to agents that disrupt the synthesis of myelin components, the best example of which is diphtheria toxin, which has access to peripheral nerves where it inhibits Schwann cell protein synthesis and causes primary demyelina-tion. Oligodendrocyte demyelination can be induced experimentally by diphtheria toxin and by other... 

A novel derivative of histidine present only in the eukaryotic protein elongation factor 2 (EF-2), which participates in the elongation step of protein biosynthesis. Diphtheria toxin inhibits eukaryotic protein synthesis by catalyzing a covalent modification of diphthamide (see Chapter 25). 

The actions of diphtheria and pertussis toxins are also mediated by ADP-ribosylation. Diphtheria toxin inhibits eukaryotic protein synthesis by ADP ribosylation of elongation factor II (Chapter 23). Pertussis toxin inactivates Gi by ADP ribosylation of its A-subunit and causes an increase in cAMP production. Unlike cholera toxin, pertussis and diphtheria toxins gain access to many tissues to produce diverse biological effects. Severe watery diarrhea... 

A group of plant lectins, such as abrin, ricin, and mod-eccin, are highly toxic to eukaryotic cells. Their mode of action consists of inhibition of protein synthesis by enzymatically inactivating the EF-2 binding region of the 60S ribosomal subunit, whereas the diphtheria toxin inactivates the EF-2 protein itself. Ricin is isolated from castor beans and has a molecular weight of 66,000. Like most plant and bacterial toxic proteins, ricin contains two... 

Many clinically important antibiotics function by inhibiting protein synthesis. All steps of protein synthesis are susceptible to inhibition by one antibiotic or another. Diphtheria toxin inhibits protein synthesis by covalently modifying an elongation factor, thereby preventing elongation. Ricin, a toxin from castor beans, inhibits elongation by removing a crucial adenine from rRNA. 

Diphtheria is an acute illness caused by the toxin released by a Corynebacterium diphtheriae infection. The toxin inhibits cellular protein synthesis, with membranes forming on mucosal surfaces. Systemic toxemia can result in myocarditis, neuritis, and thrombocytopenia. Membrane formation can cause respiratory obstruction, and significant toxin absorption can lead to severe illness and death. 

A. Diphtheria toxin has two subunits. The B subunit binds to a cell surface receptor and facilitates the entry of the A subunit into the cell. The A snbnnit then catalyzes the ADP-ribosylation of elongation factor 2 (EF2). EF2 is thus inhibited from participating in the translocation process of protein synthesis hence, protein synthesis stops. 

Diphtheria toxin is one of the most potent toxins known a single molecule of diphtheria toxin is sufficient to inactivate enough eukaryotic elongation factor eEF-2 in a cell to cause death. Ricin is derived from castor beans and its mode of action is to inactivate eukaryotic 28S rRNA molecules by removing a single adenine residue by N-glycolytic cleavage. The other inhibitor of eukaryotic protein synthesis shown in Table 26.1 is cycloheximide, which inhibits peptidyl transferase activity of the 60S ribosome subunit. 

Denileukin diftitox Targeted diphtheria toxin with inhibition of protein synthesis 9-18 pg/kg per day IV for the first 5 days every 3 weeks Fever arthralgia asthenia hypotension... 

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