Corynebacterium diphtheriae Diphtheria toxin

Corynebacterium diphtheriae Diphtheria toxin Delivery of peptides into MHC class 1 pathways" ... 

One of the primary killers of children prior to immunization was upper respiratory tract infections by Corynebacterium diphtheriae. Toxin produced by a lysogenic phage that is carried by some strains of this bacteria causes the lethal effects. It is lethal in small amounts because it blocks protein synthesis. The viral toxin is composed of two parts. The B portion binds a cell s surface and injects the A portion into the cytosol of cells. The A portion ADP-ribosylates a histidine-derived residue of the elongation factor 2 (EF-2) known as diphthamide. This action completely blocks the ability of EF-2 to translocate the growing polypeptide chain. 

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. 

Detoxification. The process by which bacterial toxins are converted to harmless toxoids. Formalin is used to detoxify the toxins of both Corynebacterium diphtheriae and Clostridium tetani. The detoxification may be performed either on the whole culture in the fermenter or on the purified toxin after fractionation. 

Clinically, monoclonal antibodies are also proposed as drug delivery vehicles in certain tumors where specific tumor-associated antigens are expressed. In this context, investigators have found that by conjugating toxins such as the A chain polypeptide of the plant protein ricin or the bacterial toxin from Corynebacterium diphtheriae to monoclonal antibodies specific for certain tumor type, as few as one or two molecules of antibody-toxin conjugate can destroy a tumor cell in vitro. Some success has also been obtained in clinical trials with monoclonal antibody-toxin conjugates. 

Diphtheria and tetanus vaeeine are two eommonly used toxoid-based vaccine preparations. The initial stages of diphtheria vaccine production entails the growth of Corynebacterium diphtheriae. The toxoid is then prepared by treating the active toxin produced with formaldehyde. The product is normally sold as a sterile aqueous preparation. Tetanus vaccine production follows a similar approach Clostridium tetani is cultured in appropriate media, the toxin is recovered and inactivated by formaldehyde treatment. Again, it is usually marketed as a sterile aqueous-based product. 

IL-2, rDNA/Seragen [BIO] A-L-Methionyl-387-L-histidine-388-L-alanuie-l-388-toxin (Corynebacterium diphtheriae strain Cl) (388-2 ) protein with 2-133-interleukin 2 (human clone pTIL2-21a) [CAS] Interleukin-2 Fusion Protein [SY] Interleukin-2/diphtheria toxin fusion protein, recombinant [SY]... 

Toxins from Corynebacterium diphtheriae or Clostridium tetani are water soluble proteins, which effectively constitute the respective vaccine antigens. However, they are treated with formaldehyde to eliminate or reduce the associated toxicity to... 

Diphtheria toxin, produced by Corynebacterium diphtheriae, is a single polypeptide (Mr = 63,000) with two intrachain disulfide bridges. A portion of the molecule, the A fragment (Mr = 21,000), must enter the cytoplasm of a cell to exert the toxic effect. Through a fairly complex mechanism, the larger molecule is cleaved into two on the membrane surface to yield A and B fragments. The latter facilitates entry of the A fragment into the... 

Shiloach, J., and Kaufman, J. B. (1999). The combined use of expanded bed adsorption and gradient elution for capture and partial purification of mutant diphtheria toxin (CRM 9) from Corynebacterium diphtberiae. Sep. Sci. Technol. 34, 29-40. 

Bacteria are both harmful and beneficial. They degrade the waste-products produced by society. They are used in wastewater treatment plants— thus, they are beneficial. On the other hand, they can also be pathogenic. The bacteria. Salmonella typhosa, causes typhoid fever Shigella flexneri causes bacillary dysentery. Clostridium tetani excretes toxins producing tetanus. Clostridium botulinum excretes the toxin causing botulism. Corynebacterium diphtheriae is the agent for diphtheria. 

Diphtheria (Corynebacterium diphtheriae). Antitoxin 10 000-100 000 units i.v. in two divided doses 0.5-2 h apart is given to neutralise toxin already formed according to the severity of the disease. Erythromycin or benzylpenicillin is also used, to prevent the production of more toxin by destroying the bacteria. 

Diphtheria toxin is the main pathogenicity factor in diphtheria (Pappen-heimer, 1977). The toxin gene is carried by a bacteriophage, p, which is lysogenic in Corynebacterium diphtheriae. Toxigenic strains of the bacteria cause local infection of the throat. After recovery from the acute phase of the disease, life-threatening organ complications often occur, mainly in the heart, which are due to toxin produced by the bacteria in the throat and released into the circulation. Due to mass vaccination, the disease is now almost extinct in developed countries. 

Detoxification. The process by which bacterial toxins are converted to harmless toxoids. Formaldehyde is used to detoxify the toxins of Corynebacterium diphtheriae, Clostridium botu-linum and Cl. tetani. The detoxification may be performed either on the whole culture in the fermenter or on the purified toxin after fractionation. Traditionally the former approach has been adopted, as it is much safer for the operator. However, the latter gives a purer product. The pertussis toxin used in acellular vaccines may be detoxified with formaldehyde, glutaraldehyde, or both, hydrogen peroxide or tetranitromethane. In the case of genetically detoxified pertussis toxin, a treatment with a low concentration of formaldehyde is still performed to stabilize the protein. 

A-B Toxins are bacterial toxins composed of two peptide chains one (B) that binds to the invaded cell surface, and the other (A) containing the toxin which is then taken-up into the cell. Some examples of exotoxins secreted by the bacteria into the surrounding medium and highly toxic to certain tissues are pathogens causing botuiism (Clostridium botulinum), tetanus (Clostridium tetani) and diptheria (Corynebacterium diphtheria. An example of an A-B endotoxin is Vibrio cholerae. Botulinum toxin and tetanus toxin have their main toxic actions on neuronal tissues, so are described at NEUROTOXINS. 

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. 

Toxins capable of catalyzing such a reaction include diphtheria toxin, secreted by lysogenic strains of Corynebacterium diphtheriae carrying the phage-encoded toxin gene (DT), and the exotoxin A from Pseudomonas aeruginosa (ETA). Both catalyze the ADP-ribosylation of a posttranslationally-modified histidine residue (called diphthamide) in EF-2. 

Many toxins interfere with intracellular functions. The best-characterized of these are diphtheria toxin and cholera toxin, produced by the bacteria Corynebacterium diptheriae and Vibrio cholerae, respectively. Both of these toxins contain two subunits, called A and B. The A subunit is responsible for the toxic effect, whereas the B subunit binds to the target cell. Once diphtheria toxin has entered the target cell, the A and B subunits split apart. The A subunit, which is an enzyme, catalyzes a reaction that prevents protein synthesis. The cell dies because it cannot synthesize proteins. The host organisms dies because cardiac, kidney, and nervous tissue are destroyed. 

Tetanus and diphtheria toxoids indnce antibodies against toxins made by Corynebacterium diphtherias and Clostridium tetani. It is indicated for achievement of active immunity against diphtheria and tetanus. Tetanus and diphtheria toxoids (Td) for adult use are the preferred agents for immunizing most adults and children after 7 years. 

Inhibitors of translation - A number of the common inhibitors of prokaryotic translation are also effective in eukaryotic cells. They include pactamycin, tetracycline, and puromycin. Inhibitors that are effective only in eukaryotes include cycloheximide and diphtheria toxin. Cycloheximide inhibits the peptidyltransferase activity of the eukaryotic ribosome. Diphtheria toxin is an enzyme, coded for by a bacteriophage that is lysogenic in the bacterium Corynebacterium diphtheriae. It catalyzes a reaction in which NAD+ adds an ADP ribose group to a specially modified histidine in the translocation factor eEF2, the eukaryotic equivalent of EF-G (Figure 28.36). Because the toxin is a catalyst, minute amounts can irreversibly block a cell s protein synthetic machinery. As a result, pure diphtheria toxin is one of the most deadly substances known. 

White and Ringe (Chapter 21) describe a new, metal-dependent mode of protein-DNA interaction, which was revealed by X-ray crystallographic studies of the diphtheria toxin repressor (DtxR). This protein is activated in the presence of iron, an adaptative response of Corynebacterium diphtheriae to low iron concentrations. 

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