Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.69 (botulinum neurotoxin)
 1,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Botulinum neurotoxin (BoNT) is one of the most potent toxins known. BoNT is also a food poison, which means that the toxin must survive the protease action and acidity of the gut. A group of neurotoxin-associated proteins which are only beginning to be identified and characterized are believed to be responsible for this protection. Hn-33 is a 33 kDa polypeptide which is a major component of the type A botulinum neurotoxin complex. Crystals of Hn-33 have been grown by vapour-diffusion techniques. They belong to a primitive orthorhombic space group and diffract to a resolution of 2. 6 A, with unit-cell parameters a = 130.3, b = 122.2, c = 37.2 A.
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PMID:Preliminary crystallographic studies of a protease resistant botulinum neurotoxin associated protein Hn-33. 1032 96

Clostridium botulinum serotype A produces a neurotoxin composed of a 100-kDa heavy chain and a 50-kDa light chain linked by a disulfide bond. This neurotoxin is part of a ca. 900-kDa complex, formed by noncovalent association with a single nontoxin, nonhemagglutinin subunit and a family of hemagglutinating proteins. Previous work has suggested, although never conclusively demonstrated, that neurotoxin alone cannot survive passage through the stomach and/or cannot be absorbed from the gut without the involvement of auxiliary proteins in the complex. Therefore, this study compared the relative absorption and toxicity of three preparations of neurotoxin in an in vivo mouse model. Equimolar amounts of serotype A complex with hemagglutinins, complex without hemagglutinins, and purified neurotoxin were surgically introduced into the stomach or into the small intestine. In some experiments, movement of neurotoxin from the site of administration was restricted by ligation of the pylorus. Comparison of relative toxicities demonstrated that at adequate doses, complex with hemagglutinins, complex without hemagglutinins, and pure neurotoxin can be absorbed from the stomach. The potency of neurotoxin in complex was greater than that of pure neurotoxin, but the magnitude of this difference diminished as the dosage of neurotoxin increased. Qualitatively similar results were obtained when complex with hemagglutinins, complex without hemagglutinins, and pure neurotoxin were placed directly into the intestine. This work establishes that pure botulinum neurotoxin serotype A is toxic when administered orally. This means that pure neurotoxin does not require hemagglutinins or other auxiliary proteins for absorption from the gastrointestinal system into the general circulation.
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PMID:Pure botulinum neurotoxin is absorbed from the stomach and small intestine and produces peripheral neuromuscular blockade. 1045 20

The cause of grass sickness, an equine dysautonomia, is unknown. The disease usually results in death. Gastrointestinal (GI) dysfunction is a common clinical manifestation in all forms of the disease. It is generally thought that equine grass sickness (EGS) is caused by an ingested or enterically produced neurotoxin which is absorbed through the GI tract. Clostridium botulinum was first implicated as a causative agent when it was isolated from the GI tract of a horse with EGS in 1919. The aim of the present study was to investigate the hypothesis that EGS results from toxicoinfection with C. botulinum type C: growth of the bacterium in the GI tract with production of toxin (BoNT/C). Ileum contents and faeces from horses with EGS were investigated for BoNT/C, and indirectly for the presence of C. botulinum type C, and compared with control samples from horses without EGS. BoNT/C was detected directly by ELISA in the ileum of 45% (13/29) of horses with EGS compared to 4% (1/28) of controls, and in the faeces of 44% (20/45) of horses with EGS compared to 4% (3/77) of controls. Levels of up to 10 Mlg toxin/g wet weight of gut contents were observed. The one control horse with detectable toxin in the ileum had been clinically diagnosed as having acute EGS, but this was not confirmed by histopathology. The organism was detected indirectly by assaying for BoNT/C by ELISA after enrichment in culture medium. C. botulinum type C was shown to be present in 48% (14/29) of ileum samples and 44% (20/45) of faecal samples from horses with EGS, compared with 7% (2/27) of ileum samples and 8% (6/72) of faecal samples from controls. These results support the hypothesis that EGS results from a C. botulinum type C toxicoinfection.
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PMID:The association of Clostridium botulinum type C with equine grass sickness: a toxicoinfection? 1059 23

More than fifty years following the discovery that botulinum neurotoxins inhibit neuromuscular transmission, these powerful poisons have become drugs with many indications. First used to treat strabismus, local injections of botulinum neurotoxin are now considered a safe and efficacious treatment for neurological and non-neurological conditions. One of the most recent achievements in the field is the observation that botulinum neurotoxin is a treatment for diseases of the gastrointestinal tract. Botulinum neurotoxin is not only potent in blocking skeletal neuromuscular transmission, but also block cholinergic nerve endings in the autonomic nervous system. The capability to inhibit contraction of smooth muscles of the gastrointestinal tract was first suggested based on in vitro observations and later demonstrated in vivo; it has also been shown that botulinum neurotoxin does not block non adrenergic non cholinergic responses mediated by nitric oxide. This has further promoted the interest to use botulinum neurotoxin as a treatment for overactive smooth muscles and sphincters, such as the lower esophageal sphincter to treat esophageal achalasia, or the internal anal sphincter to treat anal fissure. Information on the anatomical and functional organization of innervation of the gastrointestinal tract is a prerequisite to understand many features of botulinum neurotoxin action on the gut and the effects of injections placed into specific sphincters. This review presents current data on the use of botulinum neurotoxin to treat diseases of the gastrointestinal tract and summarizes recent knowledge on the pathogenesis of disorders of the gut due to a dysfunction of the enteric nervous system.
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PMID:Gastrointestinal smooth muscles and sphincters spasms: treatment with botulinum neurotoxin. 1267 92

Botulism is caused by the blockage of the neural transmission in the cholinergic synapses by botulinum neurotoxin (BoNT) which is produced by Clostridium botulinum or other Clostridia. The classic form of botulism occurs after the ingestion of food contaminated by BoNT. The course of the infection can be asymptomatic, mild with subtle paralysis ("failure to thrive") oder severe with generalized paralysis ("floppy infant"). Infected infants can also die sudden and unexpectedly. These deaths often are attributed to Sudden Infant Death Syndrome (SIDS), unless a thorough postmortem examination reveals Botulism. The rate of fatal Botulism falsely attributed to SIDS is not known, because it is difficult in most cases to show the causal relationship between contamination, disease and death. We report the sudden and unexpected simultaneous death of twins of 22 months which could be attributed to Botulism. Contamination of food, colonization of the gut by Clostridia and infection with specific pathomorphological changes could be proven. The initial suspicion of infanticide could be excluded. lt could be shown, that Botulism is a potential cause of simultaneous unexpected deaths in twins.
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PMID:[Sudden death of twins: botulism because of contamination by pap vegetables]. 1474 69

Local injections of botulinum neurotoxin are now considered an efficacious treatment for neurological and non-neurological conditions. One of the most recent achievements in the field is the observation that botulinum neurotoxin provides benefit in diseases of the gastrointestinal tract. Botulinum neurotoxin inhibits contraction of gastrointestinal smooth muscles and sphincters; it has also been shown that the neurotoxin blocks cholinergic nerve endings in the autonomic nervous system, but it does not block nonadrenergic responses mediated by nitric oxide. This aspect has further promoted the interest to use botulinum neurotoxin as a treatment for overactive smooth muscles, such as the anal sphincters to treat anal fissure and outlet-type constipation, or the lower esophageal sphincter to treat esophageal achalasia. Knowledge of the anatomical and functional organization of innervation of the gastrointestinal tract is a prerequisite to understanding many features of botulinum neurotoxin action on the gut and the effects of injections placed into specific sphincters. This review presents current data on the use of botulinum neurotoxin to treat diseases of the gastrointestinal tract and summarizes recent knowledge on the pathogenesis of disorders of the gut due to a dysfunction of the enteric nervous system.
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PMID:Treatment with botulinum neurotoxin of gastrointestinal smooth muscles and sphincters spasms. 1502 68

Botulinum neurotoxins are multifaceted molecules, which are truly unique not only in their mode of action, but also their utility as a drug carrier either across the gut wall or to the nerve terminals. The molecule is divided in clear functional domains that can operate independently. This feature can be used to employ them as cargo carrier by linking other drugs or vaccines with the binding and translocation domains of BoNT. While the domain structures are largely independent of each other, the dynamic structure of these domains, especially that of the enzymatic domain (L chain), is quite different from the reported crystal structures for several BoNT serotypes and their enzymatic domain. This review discusses the comparative structures of BoNT in crystal and solution for their relevance to the molecular mechanism of BoNT action, especially in view of our recent discovery that the enzymatically active structure of the BoNT exists as a molten-globule and that of the endopeptidase domain as a novel PRIME conformation. Finally, a non-exhaustive discussion has been included to explain the long-lasting biological effects of certain serotypes of BoNT, based on the current knowledge of the structure-function of different serotypes of botulinum neurotoxins.
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PMID:Botulinum neurotoxin structure, engineering, and novel cellular trafficking and targeting. 1678 3

Orally ingested botulinum neurotoxin (BoNT) causes food-borne botulism, but BoNT must pass through the gut lining and enter the bloodstream. We have previously found that type B haemagglutinin (HA) proteins in the toxin complex play an important role in the intestinal absorption of BoNT by disrupting the paracellular barrier of the intestinal epithelium, and therefore facilitating the transepithelial delivery of BoNT. Here, we show that type A HA proteins in the toxin complex have a similar disruptive activity and a greater potency than type B HA proteins in the human intestinal epithelial cell lines Caco-2 and T84 and in the canine kidney epithelial cell line MDCK I. In contrast, type C HA proteins in the toxin complex (up to 300 nM) have no detectable effect on the paracellular barrier in these human cell lines, but do show a barrier-disrupting activity and potent cytotoxicity in MDCK I. These findings may indicate that type A and B HA proteins contribute to the development of food-borne botulism, at least in humans, by facilitating the intestinal transepithelial delivery of BoNTs, and that the relative inability of type C HA proteins to disrupt the paracellular barrier of the human intestinal epithelium is one of the reasons for the relative absence of food-borne human botulism caused by type C BoNT.
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PMID:Disruption of the epithelial barrier by botulinum haemagglutinin (HA) proteins - differences in cell tropism and the mechanism of action between HA proteins of types A or B, and HA proteins of type C. 1911 44

Infant botulism is a rare disease in the UK, with the first case being recognized in 1978 and only five subsequent cases being reported before 2007. This study reports two unlinked cases of infant botulism, caused by two distinct strains of Clostridium botulinum (toxin types A and B, respectively), that occurred within a single month in the south-east of England in October 2007. The use of real-time PCR to detect C. botulinum neurotoxin genes in clinical specimens to improve the diagnostic procedure and to follow carriage of the causative organism in the infant gut is described. The laboratory investigation of these two cases demonstrated that a combination of the mouse bioassay, real-time PCR assays and conventional microbiological culture can provide rapid confirmation of a clinical diagnosis and affect patient management. Both infants (aged 4 and 8 months) were previously healthy prior to the onset of symptoms, and in both cases, a diagnosis of infant botulism was delayed for at least 10 days after initial admission to hospital. Once diagnosed, one of the infants was the first in the UK to be treated with human-derived botulism immunoglobulin. Real-time PCR was used to demonstrate that C. botulinum was excreted in the infants' faeces for up to 68 and 81 days, respectively. Despite the infrequency of infant botulism in the UK, clinicians should be aware of this rare but serious condition and should seek microbiological advice when presented with young infants with compatible symptomologies.
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PMID:Report of two unlinked cases of infant botulism in the UK in October 2007. 1966 Dec 2

Clostridium tetani and Clostridium botulinum produce two of the most potent neurotoxins known, tetanus neurotoxin and botulinum neurotoxin, respectively. Extensive biochemical and genetic investigation has been devoted to identifying and characterizing various C. botulinum strains. Less effort has been focused on studying C. tetani likely because recently sequenced strains of C. tetani show much less genetic diversity than C. botulinum strains and because widespread vaccination efforts have reduced the public health threat from tetanus. Our aim was to acquire genomic data on the U.S. vaccine strain of C. tetani to better understand its genetic relationship to previously published genomic data from European vaccine strains. We performed high throughput genomic sequence analysis on two wild-type and two vaccine C. tetani strains. Comparative genomic analysis was performed using these and previously published genomic data for seven other C. tetani strains. Our analysis focused on single nucleotide polymorphisms (SNP) and four distinct constituents of the mobile genome (mobilome): a hypervariable flagellar glycosylation island region, five conserved bacteriophage insertion regions, variations in three CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) systems, and a single plasmid. Intact type IA and IB CRISPR/Cas systems were within 10 of 11 strains. A type IIIA CRISPR/Cas system was present in two strains. Phage infection histories derived from CRISPR-Cas sequences indicate C. tetani encounters phages common among commensal gut bacteria and soil-borne organisms consistent with C. tetani distribution in nature. All vaccine strains form a clade distinct from currently sequenced wild type strains when considering variations in these mobile elements. SNP, flagellar glycosylation island, prophage content and CRISPR/Cas phylogenic histories provide tentative evidence suggesting vaccine and wild type strains share a common ancestor.
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PMID:Comparative pathogenomics of Clostridium tetani. 2880 May 85


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