Botulinum toxins from Clostridium botulinum are the most toxic proteins known to date but have, nevertheless, found widespread pharmaceutical and cosmetic use. Botulinum toxin type A (BTX-A) was approved in 1989 for the treatment of strabismus and in 2002 as a cosmetic against glabellar lines. Meanwhile, the use of BTX-A has been extended to the treatment of numerous other disorders resulting from hyperactive skeletal or smooth muscles, hypersecretory and painful disorders, and serotype B (BTX-B) was approved for treatment of cervical dystonia in 2000. Subcutaneous and intramuscular injections of BTX-A figure among the most popular cosmetic treatments worldwide (Lim and Seet 2007).
BTX-A consists of two polypeptide chains that are connected by a disulfide bridge. The 100-kDa heavy chain confers binding to proteins located in the presyn-aptic membrane of neuromuscular junctions and subsequent neuronal internalization by endocytosis. Upon reduction of the disulfide bond, the 50-kDa light chain escapes from endocytotic vesicles and proteolytically degrades SNAP 25. Other botulinum toxins, known as serotypes B-G, share the same two-chain structure and a similar route of cellular uptake but proteolyze different components of the SNARE complex: type E also attacks SNAP 25, type C targets both SNAP 25 and synaptobrevin, whereas types B, D, F, and G degrade synaptobrevin (Jahn and Niemann 1994). Whichever SNARE protein is the target of the proteolytic attack, botulinum toxins consistently prevent presynaptic vesicles from docking to and fusing with the presynaptic plasma membrane to release acetylcholine neurotrans-mitter into the neuromuscular junction, which causes flaccid muscular paralysis that can persist for up to several months.
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