| COMMENTS |
Inhalation anthrax, the most serious type of anthrax infection, begins when inhaled B. anthracis spores are ingested by immune-system macrophages in the lungs. Macrophages normally destroy such invaders, but in this case the spores kill the macrophages instead. The bacterium then finds its way into the bloodstream, where it secretes the three-comp. anthrax toxin Protective antigen forms a membrane-inserting heptamer that makes it possible for the other 2 proteins to enter target cells. Lethal factor then dis Rupts a key cell-signaling pathway & kills immunbe-system cells |
| MECHANISM OF ACTION |
Key element in being able to determine structure of protein, was the realizat ion that its catalytic portion could be crystallized, even though the entire protein was extremely resistant to crystallization. Mechanism of action involves recruitment of the endogenous regulatory protein calmodulin. Edema factor not only binds calmodulin, sequestering it & preventing it from carrying out its signal transduction functions & other normal roles, but binding of calmodulin also converts it into a active conspira tor in edema factor’s toxic mission. Researchers have now discovered exactly how this occurs by analyzing crystal structures they obtained of edema factor’s catalytic region with & without calmodulin. Their study shows that binding calmodulin induces a major confo rmational rearrangement of edema factor’s catalytic domain. The rearrange ment makes the enzyme highly efficient at catalyzing the conversion of ATP into cyclic AMP. The resulting overproduction of cyclic AMP causes cell death & fluid accumulation (edema) that contribute to anthrax infection. The structure of edema factor is sufficiently different from the structures of human & animal enzymes of the same class – the adenylyl cyclases – that edema factor might be easy to block selectively with a small molecule drug |
| UPDATE | 01.02 |
| AUTHOR | This data is not available for free |
| LITERATURE REF. | This data is not available for free |
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