R l i i hn i

2 457 458 864

Figure 5 Structure/nomenclature of tetanus and botulinum toxins. sc-TeTx, single chain non-cleaved tetanus toxin; TeTx. tetanus toxin after proteolytic activation; L and H, intact light and heavy chains respectively; L-HN(4M.a64)TeTx, intact L chain linked to a fragment of H chain (from residue 458 at the N-terminal end to residue 864); HN and Hc, N-termlnal and C-terminal parts respectively of the H chain. The corresponding nomenclature for botulinum toxin type A is BoNT/A, and for type B, BoNT/B. etc (Reproduced with permission from Mims et at, 1995 )

Binary toxins

Bacillus antbracis produces two binary toxins: edema factor (EF) and lethal factor (LF). For both toxins, protective antigen (PA) is required for activity by promoting entry of either EF or LF (but not both simultaneously) into the cytosol of susceptible cells. (Historically, these proteins were first described as factors I (EF), II (PA) and III (LF) and perceived as forming a tripartite synergisticallv acting toxin. (Current usage favours EF, PA, LF and a duality of binary toxins: PA+EF; PA4-LF.) Current perceptions on the mode of action of these binary toxins are based on effects seen in cultured cells. PA binds to cell membranes, undergoes proteolytic activation by furin and internalization into an acidified endosome. Activated PA oligomerizes into a heptamcric ring structure to which either EF or LF will bind in a competitive manner. The heptamer acts as a pore-forming complex aiding the translocation of EF or LF into the cytosol. EF is an inactive adenylate cyclase which becomes activated by calmodulin, leading to supraphysiological levels of cAMP. The known secretagogue activity of cAMP (can induce fluid secretion) could explain both the edematous reaction evoked in skin tests and the lethal systemic effccts of anthrax. In guinea pigs, lethality was shown to be due to secondary oligemic shock. The action of anti-PA (PA is a protective immunogen) may be interpreted in terms of antibodies preventing the initial binding of PA, or the binding of EF or LF to PA. The binding of F.F is

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