Anthrax toxin entry

Protein toxins acting intracellularly are often composed of two subunits (A/B model). One subunit is catalytic (A-subunit) and the other is responsible for binding and cell entry (B-subunit). Following binding to an extracellular membrane receptor, the toxins are endocytosed. From the endosomes, the A-subunit is directly (pH dqDendent) transferred into the cytosol (e.g., diphtheria toxin and anthrax toxin) or the toxin is transported in a retrograde manner via the golgi to the ER (e.g., cholera toxin), where translocation into the cytosol occurs [1]. 

Endocytosis may not be required for the entry of an invasive adenylate cyclase from Bordello pertussis (Hanski and Ferfel, 1985 Donovan and Storm, 1990). This is a single chain protein (mol. wt. approx. 200 kDa) which resembles the edema factor from anthrax toxin in that it must interact with calmodulin to become active. In contrast to anthrax toxin, it consists of only one polypeptide which is, however, easily cleaved by proteases and thereby activated. An enzymatically active 45 kDa fragment is not active on whole cells, but it could in conjunction with the rest of the molecule enter the cytosol. The facts that this toxin acts much more rapidly than anthrax toxin, and that it is active even at 4 °C and on erythrocytes that have little, if any, endocytosis, suggest that the toxin is able to penetrate directly through the cell surface membrane. 

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. 

Edema Toxin (EdTx) and Lethal Toxin (LeTx) are two toxins with immunomodulatory activity that are produced by A anthracis, the cause of the disease anthrax. Both toxins are composed of a heptameric complex of protective antigen (PA) bound to either edema factor (EF) or lethal factor (LF). " The heptameric complex of PA is responsible for receptor binding and cellular entry, whereas toxicity is associated with both EF, a calmodulin-dependent adenylate cyclase that induces increases in cytosolic cAMP and LF, a metalloprotease that cleaves mitogen-activated protein kinase kinases (MAPKK). ... 

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