Snake venom neurotoxins

Tsernoglou, D., Petsko, G. A., McQueen Jr., J. E. and Hermans J. (1977). Molecular graphics application to the structure determination of a snake venom neurotoxin. Science 197,1378-1380. 

Structure of erabutoxin b. Many snake venom neurotoxins have similar structures with conserved disulfide bridge positions. See Hatanaka, H. et. al.513... 

Despite extensive studies on acetylcholine receptor (AChR) and snake venom neurotoxins(23,24), direct evidence is lacking as to what region of the neurotoxin molecule the receptor bind to. The availability of series of neurotoxin II derivatives with spin or fluorescence labels in known positions provides the means for outlining the topography of a neurotoxin binding site. 

Neurotoxins present in sea snake venoms are summarized. All sea snake venoms are extremely toxic, with low LD5Q values. Most sea snake neurotoxins consist of only 60-62 amino acid residues with 4 disulOde bonds, while some consist of 70 amino acids with 5 disulfide bonds. The origin of toxicity is due to the attachment of 2 neurotoxin molecules to 2 a subunits of an acetylcholine receptor that is composed of a2 6 subunits. The complete structure of several of the sea snake neurotoxins have been worked out. Through chemical modification studies the invariant tryptophan and tyrosine residues of post-synaptic neurotoxins were shown to be of a critical nature to the toxicity function of the molecule. Lysine and arginine are also believed to be important. Other marine vertebrate venoms are not well known. 

All sea snakes are poisonous and their venoms are extremely toxic. The LD q for crude sea snake venom can be as low as 0.10 fig/g mouse body weight (i). For purified toxin the LD q is even lower, suggesting the high toxicity of sea snake toxins and venoms. This toxicity is derived from the presence of potent neurotoxins. Compared to snake venoms of terrestrial origin, sea snake venoms have been studied less. Different enzymes reported to be present or absent are summarized in Table I. 

Before discussing the structure of the neurotoxins, it is necessary to define the types of neurotoxins. Three types of neurotoxins have been found so far in snake venoms. The first one is a postsynaptic neurotoxin, the second is a presynaptic neurotoxin, and the last is a cholinesterase inhibiting neurotoxin. Most sea snake venoms seem to contain only the postsynaptic neurotoxin. Only in Enhydrina... 

Another type of neurotoxin found in sea snake venoms is a hybrid type structurally situated between the short-chain and long-chain types. As can be seen in Table IV, two toxins shown here have a long stretch of segment 4, yet there is no disulfide bond in this portion. 

The similarity of the primary structure of different sea snake venoms has already been discussed. Postsynaptic neurotoxins from Elapidae venom have been extensively studied. Elapidae include well-known snakes such as cobra, krait, mambas, coral snakes, and all Australian snakes. Like sea snake toxins, Elapidae toxins can also be grouped into short-chain (Type I) and long-chain (Type II) toxins. Moreover, two types of neurotoxins are also similar to cardiotoxins, especially in the positions of disulfide bonds. However, amino acid sequences between cardiotoxins and sea snake and Elapidae neurotoxins are quite different. In comparing the sequence of sea snake and Elapidae neurotoxins, there is a considerable conservation in amino acid sequence, but the difference is greater than among the various sea snake toxins. 

Since predators of snakes (and humans) have to deal with snake venoms as defenses, they are included here, even though they serve in predation. Snake venoms are primarily enzymes (proteins), especially of the phospholipase A2 type, which breaks down cell membrane phospholipids hydrolytically. Other snake venoms such as cobrotoxin contain peptides with 60-70 amino acid residues. Pharmacologically, they have neurotoxic, cytotoxic, anticoagulant, and other effects. The neurotoxins, in turn, can have pre- or postsynaptic effects. Snake venoms with both neurotoxic and hemolytic effects on the heart are known as cardiotoxins. Cytotoxins attach to the cells of blood vessels and cause hemorrhage. Snake venom factors may stimulate or inhibit blood clotting. Finally, platelet-active factors can contribute to hemorrhage. 

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... 

Lee CY, Chang CC, Chen YM (1972) Reversibility of neuromuscular blockade by neurotoxins from elapid and sea snake venoms. Taiwan Yi Xue Hui Za Zhi 71 344-9 Lee CY, Tsai MC, Chen YM, Ritonja A, Gubensek F (1984) Mode of neuromuscular blocking action of toxic phospholipases A2 from vipera ammodytes venom. Arch Int Pharmacodyn Ther 268 313-24... 

Numerous nonenzyme polypeptides occur in snake venom. Some of these polypeptides, though by no means all, are neurotoxins. 

Ploug M, Ellis V. Structure-function relationships in the receptor for urokinase-type plasminogen activator. Comparison to other members of the Ly-6 family and snake venom alpha-neurotoxins. FEBS Lett 1994 349(2) 163-168. 

Neurotoxins fi om snake venoms have proved to be valuable tools for the understanding of synaptic transmission mechanisms. Likewise, the powerful inhibitory action of fasciculins against mammalian AChE makes them potentially useful tools for pharmacological and neurochemical research. Studies of their biochemical and elec-trophysiological effects on the central nervous system and biochemical characterization are now being carried out. 

Clinically, mamba bites may not provoke a major local reaction. If neurotoxins are injected by the bite, clinical symptoms appear within minutes to hours. Clinical signs of impairment of neuromuscular transmission (ptosis, ophthalmoplegia, bulbar symptoms, or generalized weakness) dictate administration of antivenom (Ludolfph, 2000). For Elapidae (coral snakes) venom is known that is a potential neurotoxin and may cause paresthesias, weakness, cranial nerve dysfunction, confusion, fasciculations, and lethargy. Often mild local findings, diplopia, ptosis, and dysarthria are common early symptoms. Patients die because of respiratory paralysis. In these cases, early and aggressive... 

Short Neurotoxins. The 58 snake venom short neurotoxins submitted to analysis are presented in Table II. This data base, which contains 27 inactive and 30 active toxins, was built from data reported by Karlsson (11) and Dufton et al. (12). 

Short Neurotoxins. Figure 1 shovs the fragments that were selected By the program for the QSAR equation. Figure 3 shovs the primary structure of some of the snake venoms. In these, ve have underlined the fragments that vere selected by the QSAR equation as significant to activity. 

Even snake venom has been tried. Called crotoxins, from the genus Crotalus, one of the two genera for rattlesnakes, these are neurotoxins that were found to have some sort of anticancer effect, direct or indirect, but presumably in very small concentrations. The snake in particnlar was said to be the cascabel, or Crotalus... 

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