Protein exotoxins

Diphtheria causes a demyelinative neuropathy. Coryne-bacterium diphtheriae colonizes the pharynx or open wounds, and secretes a protein exotoxin. The B subunit of this exotoxin binds to plasma membranes and facilitates entry into cytosol of the A subunit, which catalyzes ADP-ribosylation, and inactivation of an elongation factor required for protein synthesis. Cardiac muscle and Schwann cells are particularly susceptible to this toxin, and hence patients with diphtheria develop cardiomyopathy and demyelinative polyneuropathy [20]. While diphtheria is now uncommon because of childhood immunization against C. diphtheriae, the disruption in preventative medicine programs caused by disintegration of the Soviet Union was followed by a substantial incidence of diphtheritic polyneuropathy in Russia. 

Cholera is a condition caused by a protein exotoxin produced by the bacterium vibrio cholerae. This protein toxin consists of six subunits one A subunit and five B subunits. The B subunits are responsible for the binding of the toxin to cAMP-functioning cells in small bowel of the intestines. The A subunit penetrates the cell and has catalytic activity which attaches the ADP portion of naturally occurring NAD (nicotine-adenosine dinucleotide) to the G-protein complex thereby inhibiting its GTPase activity. This deprives the complex of its "off-switch" for cAMP formation. The effect is the uncontrolled... 

B anthracis possesses three known virulence factors an antiphagocytic capsule and two protein exotoxins, called the lethal and the edema toxins. The role of the capsule in pathogenesis was demonstrated in the early 1900s, when anthrax strains lacking a capsule were shown to be avirulent.17 In more recent years, the genes encoding synthesis of the... 

The genes encoding the synthesis of the two protein exotoxins are located on a 60-kb plasmid, distinct from that encoding for the capsule. In an environment of increased bicarbonate and carbon dioxide and increased temperature, such as is found in the infected host, there is increased transcription of the genes for synthesis of the two toxins,24-26 as well as for the capsule.27... 

Materials produced by crystalliferous bacilli which elicit a toxic response in susceptible insects may be separated into two types. The first type, the true toxins, include the crystalline protein inclusion body the parasporal body of Hannay (14)], a heat-stable, water-soluble exotoxin active against flies, a heat-stable, dialyzable water-soluble exotoxin, toxic to Lepidoptera on injection (23), and a heat-labile, water-soluble, filterable exotoxin, toxic toward larch sawfly larvae (Hymenoptera) which was reported by Smirnoff (31). 

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

Pasteurella multocida toxin (PMT) is the major pathogenic factor responsible for atrophic rhinitis, a disease which is characterized by bone loss in the nose of pigs. PMT is a 145 kDa single-chain exotoxin, which activates Goq protein (but not Gan) and stimulates phospholipase C 3. In addition, G12/i3 proteins and subsequently Rho pathways are activated. 

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. 

Very recently the protein structures of ACE with the bound inhibitors Lisinopril (Fig. 4) and Captopril were published (101,102). Also the protein structure of the LF from Bacillus anthracis (PDB-Code 1J7N) caused a sensation, which is now available to the public (Fig. 14b) (103). LF is part of the toxic exotoxin complex composed of three distinct proteins (protective antigen PA, the lethal factor LF and the edema factor EF), and is thought to be the most toxic... 

Exotoxin A diphtheriae Pseudomonas aeruginosa AB Elongation Factor-2 Inhibition of protein synthesis Pneumonia... 

Boyle, M.D.P., Romer, T.G., Meeker, A.K., and Sledjeski, D.D., Use of surface-enhanced laser desorption ionization protein chip system to analyze streptococcal exotoxin B activity secreted by Streptococcus pyogenes, ]. Microbiol. Meth., 46, 87-89, 2001. 

Exotoxin A is an NAD -dependent ADP-ribosylating protein from Pseudomonas aeruginosa. 

Rozemuller, H., W.I Rombouts, IP. Touw, D.I FitzGerald, R.I Kreitman, I. Pastan, A. Hagenbeek, and A.C. Martens, Treatment of acute myelocytic leukemia with interleukin-6 Pseudomonas exotoxin fusion protein in a rat leukemia model. Leukemia, 1996.10(11) 1796-803. 

The heat-labile E. coli enterotoxin, whose gene is carried on a plasmid, is a close relative of cholera toxin11 0 and also catalyzes ADP ribosylation of arginine 201 of the Gsa subunit.111 Bordetella pertussis, which causes whooping cough, forms a similar toxin that attacks the inhibitory regulatory protein G v as well as transducin and inactivates them by ADP ribosylation. Diphtheria toxin (Box 29-A), the exotoxin from Pseudomonas aeruginosa, and the toxin from Clostridium botulinum also catalyze ADP-ribosylation reactions.k/1 ... 

Transforming growth factor-a-Pseudomonas aeruginosa exotoxin A 40 (TGFa-PE40, Mr = 44,960) is a recombinant fusion protein synthesized in E. co/z.127,128 The growth factor moiety binds to surface epidermal growth factor (EGF) receptors on cancerous cells and is internalized where it releases the exotoxin domain into the cytosol.128 The toxin subunit catalytically inactivates the protein synthesis machinery of the cancer cell and the cell subsequently dies.129 It is a recombinant protein intended to be an anticancer therapeutic. 

Edwards, G. M., Defeo-Jones, D., Tai, J. Y., Vuocolo, G. A., Patrick, D. R., Heimbrook, D. C., and Oliff, A. (1989). Epidermal growth factor receptor binding is affected by structural determinants in the toxin domain of transforming growth factor-alpha-Psewdo-monas exotoxin fusion proteins. Mol. Cell. Biol. 9, 2860-2867. 

An example of an expanded bed process for recovery of a Pseudomonas exotoxin from an E. coli system has been recently reported in pilot plant scale.28 A single-step recovery of a secreted recombinant protein has been carried out in expanded-bed mode directly from the fermentation broth without prior cell removal. The fusion protein was designed to have relatively low isoelectric point to enable anionic exchange adsorption at pH 5.5 where most of the E. coli host proteins are not adsorbed. The gene product was secreted to the culture medium of E. coli in high yield and the recovery of the protein was 90% in one step.29... 

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