Botulinum Structure

Whelan SM, Elmore MJ, Bodsworth NJ, Brehm JK, Atkinson T, Minton NP. Molecular cloning of the Clostridium botulinum structural gene encoding the type B neurotoxin and determination of its entire nucleotide sequence. Appl Environ Microbiol. 1992 58 2345-2354. 

Another subfamily of ADP-iibosylating toxins modifies G-actin (at Argl77), thereby inhibiting actin polymerization. Members of this family are, for example, C. botulinum C2 toxin and Clostridium perfringens iota toxin. These toxins are binary in structure. They consist of an enzyme component and a separate binding component, which is structurally related to the binding component of anthrax toxin [3]. 

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. 

DasGupta, B.R., Structure and biological activity of botulinum neurotoxin, J. Physiol., 84, 220-228, 1990. 

Krieglstein, K.G., DasGupta, B.R. and Henschen, A.H., Covalent structure of botulinum neurotoxin type-A-location of sulfhydryl groups, and disulfide... 

Ledoux, D.N., Be, X.H. and Singh, B.R., Quaternary structure of botulinum and tetanus neurotoxins as probed by chemical cross-linking and native gel electrophoresis, Toxicon, 32, 1095-1104, 1994. 

Prabakaran, S., Tepp, W. and DasGupta, B.R., Botulinum neurotoxin types B and E purification, limited proteolysis by endoproteinase Glu-C and pepsin, and comparison of their identified cleaved sites relative to the three-dimensional structure of t q)e A neurotoxin, Toxicon, 39, 1515-1531, 2001. 

Sakaguchi, G., Molecular structure of Clostridium botulinum progenitor toxins, in Portland, A.L., Dowel, V.R. and Richard, I.L., eds.. Microbial Toxins in Foods and Feeds. Cellular and Molecular Modes of Action, Plenum Press, New York, pp. 173-180, 1990. 

Strains of C. botulinum produce seven antigenetically distinct neurotoxins designated as serotypes A through G. All seven serotypes have a similar structure and molecular weight, consisting of a heavy (H) chain and a light (L) chain joined by a disulfide bond. They all interfere with neural transmission by blocking the release of ACh (see Chapter 14), which is the principal neurotransmitter at the neuromuscular junction. 

Arndt JW, Yu W, Bi F, Stevens RC (2005) Crystal structure of botulinum neurotoxin type g light chain serotype divergence in substrate recognition. Biochemistry 44 9574-80 Arndt JW, Chai Q, Christian T, Stevens RC (2006a) Structure of botulinum neurotoxin type D light chain at 1.65 a resolution repercussions for vamp-2 substrate specificity. Biochemistry 45 3255-62... 

Dasgupta B (1994) Structures of botulinum neurotoxin, its functional domains, and perspectives on the cristalline type a toxin. In Jankovic J, Hallett M (eds) Therapy with botulinum toxin. Marcel Dekker, New York, pp 15-39... 

Hanna PA, Jankovic J, Vincent A (1999) Comparison of mouse bioassay and immunoprecipitation assay for botulinum toxin antibodies. J Neurol Neurosurg Psychiatry 66 612-16 Hanson MA, Stevens RC (2000) Cocrystal structure of synaptobrevin-II bound to botulinum neurotoxin type B at 2.0 A resolution. Nat Struct Biol 7 687-92 Harlow ML, Ress D, Stoschek A, Marshall RM, McMahan UJ (2001) The architecture of active zone material at the frog s neuromuscular junction. Nature 409 479-84 Harris JB (1997) Toxic phospholipases in snake venom an introductory review. Symp. zool. Soc. Lond. 70 235-50... 

Lacy DB, Tepp W, Cohen AC, DasGupta BR, Stevens RC (1998) Crystal structure of botulinum neurotoxin type a and implications for toxicity. Nat Struct Biol 5 898-902... 

Montecucco C, Schiavo G (1995) Structure and function of tetanus and botulinum neurotoxins. Q Rev Biophys 28 423-72... 

Pellizzari R, Rossetto O, Lozzi L, Giovedi S, Johnson E et al. (1996) Structural determinants of the specificity for synaptic vesicle-associated membrane protein/synaptobrevin of tetanus and botulinum type B and G neurotoxins. J Biol Chem 271 20353-8 Pellizzari R, Mason S, Shone CC, Montecucco C (1997) The interaction of synaptic vesicle-associated membrane protein/synaptobrevin with botulinum neurotoxins D and F. FEBS Lett 409 339 12... 

Sakaguchi G (1982) Clostridium botulinum toxins. Pharmacol Ther 19 165-94 Sankhla C, Jankovic J, Duane D (1998) Variability of the immunologic and clinical response in dystonic patients immunoresistant to botulinum toxin injections. Mov Disord 13 150-54 Schantz EJ, Johnson EA (1997) Botulinum toxin the story of its development for the treatment of human disease. Perspect Biol Med 40 317-27 Schiavo G (2006) Structural biology dangerous liaisons on neurons. Nature 444 1019-20 Schiavo G, Matteoli M, Montecucco C (2000) Neurotoxins affecting neuroexocytosis. Physiol Rev 80 717-66... 

Schiavo G, Papini E, Genna G, Montecucco C (1990) An intact interchain disulfide bond is required for the neurotoxicity of tetanus toxin. Infect Immun 58 4136 11 Scott AB, Magoon EH, McNeer KW, Stager DR (1989) Botulinum treatment of strabismus in children. Trans Am Ophthalmol Soc 87 174-180 discussion 180 1 Scott D (1997) Phospholipase A2 structure and catalytic properties. In Kini R (ed) Venom phospholipase A2 enzymes structure, function and mechanism. John Wiley Sons, Chichester, p 97-128. 

Segelke B, Knapp M, Kadkhodayan S, Balhorn R, Rupp B (2004) Crystal structure of Clostridium botulinum neurotoxin protease in a product-bound state evidence for noncanonical zinc protease activity. Proc Natl Acad Sci U S A 101 6888-93... 

Simpson, L.L. (1981). The origin, structure, and pharmacological activity of botulinum toxin. Pharmacol. Rev. 33 155-88. 

CWAs are represented by any one of a number of chemicals exhibiting a very high toxicity by various mechanisms. The present Handbook exhibits CWAs with structures as simple as carbon monoxide (CO) and as complex as botulinum toxin or ricin proteins. While this chapter could address the development of PBPK models of CWAs in general, the focus will primarily be on the organophosphate (OP)-based nerve agents typically represented by sarin (GB - isopropyl methylfluoro-phosphonate). 

Hambleton P. Clostridium botulinum toxins a general review of involvement in disease, structure, mode of action and preparation for clinical use. J Neurol 1992 239(l) 16-20. 

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