Abstract
Botulinum neurotoxins (BoNT) are produced by several species of clostridium. There are seven immunologically unique BoNT serotypes (A–G). The Centers for Disease Control classifies BoNTs as ‘Category A’ select agents and are the most lethal protein toxins for humans. Recently, BoNT-like proteins have also been identified in several non-clostridia. BoNTs are di-chain proteins comprised of an N-terminal zinc metalloprotease Light Chain (LC) and a C-terminal Heavy Chain (HC) which includes the translocation and receptor binding domains. The two chains are held together by a disulfide bond. The LC cleaves Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). The cleavage of SNAREs inhibits the fusion of synaptic vesicles to the cell membrane and the subsequent release of acetylcholine, which results in flaccid paralysis. The LC controls the catalytic properties and the duration of BoNT action. This review discusses the mechanism for LC catalysis, LC translocation, and the basis for the duration of LC action. Understanding these properties of the LC may expand the applications of BoNT as human therapies.
Highlights
Background on Botulinum NeurotoxinBotulinum neurotoxins (BoNT), the causative agents of botulism, are produced by several species of Clostridium, including botulinum, baratii, and butyricum
BoNT are synthesized as single chain proteins which are typically isolated as di-chain forms [16], except BoNT/E which is isolated as a single chain toxin and cleaved by host proteases into the di-chain form [16,17,18]
/G, and tetanus toxin (TeNT) cleave vesicle-associated membrane protein (VAMP)/ Synaptobrevin which is located on the cytosolic face of synaptic vesicles
Summary
Botulinum neurotoxins (BoNT), the causative agents of botulism, are produced by several species of Clostridium, including botulinum, baratii, and butyricum. BoNT/X [8], which represent potentially new BoNT serotypes. Other references that discuss and/or analyze sequence variation in the BoNT light chain include Ref. Select agents are “agents and toxins that have been determined to have the potential to pose a severe threat to public health and safety, to animal and plant health, or to animal or plant product” [11]. The CDC has catalogued select agents and toxins into three Categories A, B, and C, where Category A agents and toxins pose the greatest risk to national security [12]. Tetanus toxin and diphtheria toxin are not cataloged as a risk in the Toxins 2018, 10, 268; doi:10.3390/toxins10070268 www.mdpi.com/journal/toxins. This review will describe our current understanding of the biological and biochemical action of the LC
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