Clostridium perfringens alpha toxin
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Clinical significance
This toxin has been shown to be the key virulence factor in infection with C. perfringens; the bacterium is unable to cause disease without this toxin. Further, vaccination against the alpha toxin toxoid protects mice against C. perfringens gas gangrene. As a result, knowledge about the function of this particular protein greatly aids understanding of myonecrosis.
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Structure and homology
The alpha toxin has remarkable similarity to toxins produced by other bacteria as well as natural enzymes. There is significant homology with phospholipase C enzymes from Bacillus cereus, C. bifermentans, and Listeria monocytogenes. The C terminal domain shows similarity with non-bacterial enzymes such as pancreatic lipase, soybean lipoxygenase, and synaptotagmin I.
The alpha toxin is a zinc metallophospholipase, requiring zinc for activation. First, the toxin binds to a binding site on the cell surface. The C-terminal C2-like PLAT domain binds calcium and allows the toxin to bind to the phospholipid head-groups on the cell surface. The C-terminal domain enters the phospholipid bilayer. The N-terminal domain has phospholipase activity. This property allows hydrolysis of phospholipids such as phosphatidyl choline, mimicking endogenous phospholipase C. The hydrolysis of phosphatidyl choline produces diacylglycerol, which activates a variety of second messenger pathways. The end-result includes activation of arachidonic acid pathway and production of thromboxane A2, production of IL-8, platelet-activating factor, and several intercellular adhesion molecules. These actions combine to cause edema due to increased vascular permeability.