Botulinum Toxin - Chemical Overview and Lethality

Chemical Overview and Lethality

The seven serologically distinct toxin types are designated A through G. Additionally, six of the seven toxin types have subtypes with five subtypes of BoNT A having been described. The toxin is a two-chain polypeptide with a 100-kDa heavy chain joined by a disulfide bond to a 50-kDa light chain. This light chain is an enzyme (a protease) that attacks one of the fusion proteins (SNAP-25, syntaxin or synaptobrevin) at a neuromuscular junction, preventing vesicles from anchoring to the membrane to release acetylcholine. By inhibiting acetylcholine release, the toxin interferes with nerve impulses and causes flaccid (sagging) paralysis of muscles in botulism, as opposed to the spastic paralysis seen in tetanus.

Over 70 structures of this toxin are deposited in the PDB which reveal the tertiary structure of this class of toxins, as shown above.

It is the most acutely toxic substance known, with a median lethal dose of about 1 ng/kg when introduced intravenously and 3 ng/kg when inhaled. This means, depending on the method of introduction into the body, a mere 90–270 nanograms of botulinum toxin could be enough to kill an average 90-kg (200-lb) person, and four kg of the toxin, if evenly distributed, would be more than enough to kill the entire human population of the world.

The potency of botulinum toxin is well illustrated by this sentence from the 2011 Allergan annual report: "In 2011, we required less than a gram of raw neurotoxin to supply the world’s requirements for 25 indications approved by Government agencies around the world."

Food-borne botulism usually results from ingestion of food that has become contaminated with spores (such as a perforated can) in an anaerobic environment, allowing the spores to germinate and grow. The growing (vegetative) bacteria produce toxin. It is the ingestion of toxin that causes botulism, not the ingestion of the spores or the vegetative bacteria. Infant and wound botulism both result from infection with spores, which subsequently germinate, resulting in production of toxin and the symptoms of botulism.

Proper refrigeration at temperatures below 3°C (38°F) retards the growth of Clostridium botulinum. The organism is also susceptible to high salt, high oxygen, and low pH levels. The toxin itself is rapidly destroyed by heat, such as in thorough cooking. On the other hand, the spores that produce the toxin are heat-tolerant and will survive boiling water for an extended period of time. Fortunately, ingestion of the spores is safe, except in infants, as the highly oxygenated and highly acidic environment of an adult human digestive system prevents the spores from growing and producing the botulinum toxin.

Botulinum toxin has been recognized and feared as a potential bioterror weapon.