Anthrax exotoxins

Toxin-mediated delivery Pertussis exotoxin Anthrax exotoxin [84]... 

Classical bacterial exotoxins, such as diphtheria toxin, cholera toxin, clostridial neurotoxins, and the anthrax toxins are enzymes that modify their substrates within the cytosol of mammalian cells. To reach the cytosol, these toxins must first bind to different cell-surface receptors and become subsequently internalized by the cells. To this end, many bacterial exotoxins contain two functionally different domains. The binding (B-) domain binds to a cellular receptor and mediates uptake of the enzymatically active (A-) domain into the cytosol, where the A-domain modifies its specific substrate (see Figure 1). Thus, three important properties characterize the mode of action for any AB-type toxin selectivity, specificity, and potency. Because of their selectivity toward certain cell types and their specificity for cellular substrate molecules, most of the individual exotoxins are associated with a distinct disease. Because of their enzymatic nature, placement of very few A-domain molecules in the cytosol will normally cause a cytopathic effect. Therefore, bacterial AB-type exotoxins which include the potent neurotoxins from Clostridium tetani and C. botulinum are the most toxic substances known today. However, the individual AB-type toxins can greatly vary in terms of subunit composition and enzyme activity (see Table 2). 

C. botulinum toxins belong to the AB group of toxins, which also includes diphtheria toxin, pseudomonas exotoxin A, anthrax toxin, Shiga(like) toxin, cholera toxin, pertussis toxin, and plant toxins, e.g., ricin. Moiety A has an enzymatic activity and usually modified cellular-target entering cytosol. Moiety B consists of one or more components and binds the toxin to surface receptors, and is responsible for translocation of the A component into cells. AB toxins are produced in a non-active form and are activated by a split between two cysteine residues within a region (Falnes and Sandvig, 2000). 

Edema factor of anthrax is one of the three exotoxins produced by the bacteria. The primary sequence is only slightly homologous to other adenylyl cyclases. When it enters the host cells, edema factor acts as an adenylyl cyclase and transforms ATP to cAMP efficiently. The structme of CaM-edema factor of anthrax complex has been obtained (Figure 9). In the CaM-edema factor complex, only the C-terminal lobe binds two calcium ions while the N-terminal lobe is empty. CaM remains extended and is deeply inserted between the catalytic and the a-helical domains of this exotoxin with a large number of residues of CaM iuvolved in the interaction. CaM binding results in a large domain reorientation of edema factor. The helical domain of edema factor undergoes a 15 A translation and a 30° rotation. The CaM inserted site is far from the catalytic site and the... 

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... 

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