Lethal toxin

Important members of this toxin family are Clostridium difficile toxins A and B, which are implicated in antibiotics-associated diarrhea and pseudomembranous colitis. The large clostridial cytotoxins are single-chain toxins with molecular masses of 250-308 kDa. The enzyme domain is located at the N terminus. The toxins are taken up from an acidic endosomal compartment. They glucosylate RhoA at Thr37 also, Rac and Cdc42 are substrates. Other members of this toxin family such as Clostridium sordellii lethal toxin possess a different substrate specificity and modify Rac but not Rho. In addition, Ras subfamily proteins (e.g., Ras, Ral, and Rap) are modified. As for C3, they are widely used as tools to study Rho functions [2] [4]. 

Marine toxins are not always acutely toxic. This may be particularly so for toxins which are used to deter competing occupants for living space since they often have comparatively slow actions on growth. With such toxins, the procedures for the evaluation of acutely lethal toxins cannot apply. However, interesting discoveries may be made by using the simplest of screen of alcoholic extracts for cytolytic actions as exemplified in Table I of Shier 109),... 

Anthrax lethal factor metalloproteinase (Table 1, entry 7) Anthrax lethal factor metalloproteinase is an integral component of the tripartite anthrax lethal toxin and is required for the onset and progression of anthrax. About 300 scaffolds were selected for an NMR-based assay leading to the carboxylic acid fragment 31 [42]. Subsequent synthetic elaboration led to nanomolar inhibitors such as 32. 

Treatment—Since C. botulinum toxin blocks the actions of nerves that activate muscles necessary for breathing, an antitoxin can be injected up to about 24 hours (based on monkey studies) after exposure to a lethal toxin dose and still prevent death. The two types of available antitoxins prepared from horse sera are trivalent (includes types A, B, E) and heptavalent (types A, B, C, D, E, F, and G) preparations. It should be noted that patients face a theoretical risk of developing serum sickness from such antitoxins. 

Lethal toxin Bacillus anthracis Binary MAPKK Cell death Anthrax... 

Koya, V., Moayeri, M., Leppla, S.H., and Daniell, H. (2005). Plant-based vaccine mice immunized with chloroplast-derived anthrax protective antigen survive anthrax lethal toxin challenge. Infect. Immun. 73(12) 8266-8274. 

Performance of Random Air-Sampling Schemes. The performance of the random air-sampling schemes for evaluating acute exposures to lethal toxins and irritants is summarized in Table VII. 

Performance of Schemes Based upon Tolerance Sets and Limiting Distributions for Evaluating Acute Exposures to Lethal Toxins. [Exposure Limit = 10.0]... 

Consequently, botulinum toxin represents a strategy for dealing with spasticity that is especially problematic in specific muscles or groups of muscles. Despite the rather ominous prospect of injecting a potentially lethal toxin into skeletal muscles, this intervention has a remarkably small incidence of severe adverse effects when administered at therapeutic doses.5,44 Botulinum toxin can therefore be used as part of a comprehensive rehabilitation program to provide optimal benefits in certain patients with severe spasticity. 

Warfel JM, Steele AD, D Agnillo F (2005) Anthrax lethal toxin induces endothelial barrier dysfunction. Am J Pathol 166 1871-1881... 

Agrawal, A., Lingappa, J., Leppla, S.H., Agrawal, S., Jabbar, A., Quinn, C., Pelundran, B. (2003). Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin. Nature 424 329-34. 

Alileche, A., Serfass, E.R., Muehlhauer, S.M., Porcelli, S.A., Brojatsch, J. (2005). Anthrax lethal toxin-mediated killing of human and murine dendritic cells impairs the adaptive immune response. PLoS Pathogens 1 150-8. 

Erwin, J.L., DaSilva, L.M., Bavari, S., Little, S.F., Friedlander, A.M., Chanh, T.C. (2001). Macrophage-derived cell lines do not express proinflammatory cytokines after exposure to Bacillus anthracis lethal toxin. Infect. Immun. 69 1175-7. 

Hanna, P.C., Kochi, S., Collier, R.J. (1992). Biochemical and physiological changes induced by anthrax lethal toxin in J774 macrophage-like cells. Molec. Biol. Cell 1 7-18. 

Kirby, J.E. (2004). Anthrax lethal toxin induces human endothelial cell apoptosis. Infect. Immun. IT. 430-9. 

Klimpel, K.R., Arora, N., Leppla, S.H. (1994). Anthrax toxin lethal factor contains a zinc metalloprotease consensus sequence which is required for lethal toxin activity. Mol. Microbiol. 13 1093-1100. 

Liddington, R., Pannifer, A., Hanna, P., Leppla, S., Collier, R.J. (1999). Crystallographic studies of the anthrax lethal toxin. J. Appl. Microbiol. 87 282. 

Tan, Y., Hackett, N.R., Boyer, J.L., Crystal, D.G. (2003). Protective immunity evoked against anthrax lethal toxin after a single intramuscular administration of an adenovirus-based vaccine encoding humanized protective antigen. Hum. Gene Ther. 14 1673-82. 

Toumier, J.N., Quesnel-Hellmann, A., Mathieu, J., Montecucco, C., Tang, W.J., Mock, M., Vidal, D.R., Goossens, P.L. (2005). Anthrax edema toxin cooperates with lethal toxin to impair cytokine secretion during infection of dendritic cells. J. Immunol. 174 4934-41. 

Moayeri, M., Haines, D., Young, H.A., Leppla, S.H. (2003). Bacillus anthracis lethal toxin induces TNF-a independent hypoxia-mediated toxicity in mice. J. Clin. Invest. 112 670-82. 

Bette P, Oksche A, Mauler F, et al. (1991) A comparative biochemical, pharmacological and immunological study of Clostridium novyi alpha-toxin, C.difficile toxin B and C.sordellii lethal toxin. In Toxicon, 29 877-887. 

Giry M, Popoff MR, Eichel-Streiber Cv, et al. (1995) Transient expression of RhoA, -B, and -C GTPases in HeLa cells potentiates resistance to Clostridium difficile toxins A and B but not to Clostridium sordellii lethal toxin. In Infect Immun. 63 4063-4071. 

Popoff MR, Chaves-Olarte E, Lemichez E., et al. (1996) Ras, Rap, and Rac small GTP-binding proteins are targets for Clostridium sordellii lethal toxin glucosyla-tion. In J. Biot Chem. 271, 10217-10224. 

White applied the alkenyl-alkenyl coupling of 8 with dienyl stannane 9 under standard conditions, for the bnild np of the triene fragment of polycavernoside A (10), a lethal toxin of a red alga (Scheme 5.4.3).32 It is noteworthy that this Stille coupling was efficiently performed as the last step of the synthesis, nsing the full glycosidated aglycon 8 as the electrophilic partner. 

Spores germinate to bacillary form, multiply in macrophages, release toxins causing edema, hemorrhage, and tissue necrosis tissue damage caused by release of toxins - protective antigen, lethal toxin, edema toxin [29]... 

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