Botulinum neurotoxins substances

The botulinum neurotoxins (BoNTs) comprise a family of seven distinct neurotoxic proteins (A-G) produced by immunologically discrete strains of the anaerobic bacterium Clostridium botulinum and in rare cases by Clostridium baratii and Clostridium butyricum (Habermann and Dreyer, 1986 Harvey et ah, 2002 Simpson, 2004). These toxins act on peripheral cholinergic synapses to inhibit spontaneous and impulse-dependent release of acetylcholine (ACh) (Brooks, 1956 Kao et al., 1976). Intoxication by BoNT results in muscle weakness, which can be fatal when the diaphragm and intercostal muscles become sufficiently compromised to impair ventilation (Dickson and Shevky, 1923). The BoNTs are the most potent substances in nature, and exposure to as httle as 1-3 ng/kg may be sufficient to cause human lethahty (GUI, 1982 Middlebrook and Franz, 1997 Amon et al., 2001). 

The seven serotypes of botulinum toxin produced by Clostridium botulinum are the most toxic substances known. They are associated with lethal food poisoning after the consumption of canned foods. This family of toxins was evaluated by the United States as a potential biological weapon in the 1960s and is believed to be an agent that could be used against our troops. Unlike other threat toxins, botulinum neurotoxin appears to cause the same disease after inhalation, oral ingestion, or injection. Death results from skeletal muscle paralysis and resultant ventilatory failure. Because of its extreme toxicity, the toxin typically cannot be identified in body fluids, other than nasal... 

The mechanism whereby the bacteria produce the disease with its attendant symptoms is often due to the cells ability to produce specific poisons, toxins or aggressins (Chapter 14). Many of these are tissue-destroying enzymes which can damage the cellular structure ofthe body or destroy red blood cells. Others (neurotoxins) are highly specific poisons ofthe central nervous system, for example the toxin produced by Clostridium botulinum is, weight for weight, one ofthe most poisonous substances known. 

Classical bacterial exotoxins, such as diphtheria toxin, cholera toxin, clostridial neurotoxins, and the anthrax toxins are enzymes that modify their substrates within the cytosol of mammalian cells. To reach the cytosol, these toxins must first bind to different cell-surface receptors and become subsequently internalized by the cells. To this end, many bacterial exotoxins contain two functionally different domains. The binding (B-) domain binds to a cellular receptor and mediates uptake of the enzymatically active (A-) domain into the cytosol, where the A-domain modifies its specific substrate (see Figure 1). Thus, three important properties characterize the mode of action for any AB-type toxin selectivity, specificity, and potency. Because of their selectivity toward certain cell types and their specificity for cellular substrate molecules, most of the individual exotoxins are associated with a distinct disease. Because of their enzymatic nature, placement of very few A-domain molecules in the cytosol will normally cause a cytopathic effect. Therefore, bacterial AB-type exotoxins which include the potent neurotoxins from Clostridium tetani and C. botulinum are the most toxic substances known today. However, the individual AB-type toxins can greatly vary in terms of subunit composition and enzyme activity (see Table 2). 

The clostridial neurotoxins are the most toxic substances known to science. The neurotoxin produced from Clostridium tetani (tetanus toxin) is encountered by humans as a result of wounds and remains a serious public health problem in developing countries around the world. However, nearly everyone reared in the western world is protected from tetanus toxin as a result of the ordinary course of childhood immunizations. Humans are usually exposed to the neurotoxins produced by Clostridium botulinum (ie, the botu-linum toxins, of which there are seven in all) by means of food poisoning, although there are rare incidents of wound botulism and a colonizing infection of neonates known as infant botulism.1 Since the incidence of botulinum poisoning by all routes is very rare,... 

These are generally extracellularly liberated proteins, some of which are among the most potent tissue poisons known. Classic examples include botulinum, tetanus, diptheria and Shigella neurotoxins less potent are the haemolysins and leucocidins, produced by various streptococcal and staphylococcal species, which destroy red and white blood corpuscles, respectively. It is suggested that plaque bacteria may produce similar exotoxins although no substances specifically responsible for periodontal disease have been identified. 

The toxin BoTx, produced by the anaerobe Clostridium botulinum, has the reputation of being the most toxic substance by weight known to humans, being at least 5000 times more toxic than sarin. Botulism is a disease of both humans and animals. Seven dilferent functionally related neurotoxins are produced by various strains (A-G). Botulism is essentially an intoxication, brought on by ingestion of the toxin produced by clostridial infection of food, usually incorrectly canned meats. Primary botulism, a direct infection, is rare and only affects infants in the human species. Botulinum intoxication can, however, be treated, and this modifies the toxicity considerably. It is estimated that less than 10 % of natural cases receiving ventilatory and antitoxin support are fatal. 

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