Cone snails, toxin

A large number of toxic peptides are found in cone snails (Conidae). They include four classes of small (13-29 amino acid) basic peptides, known as conotoxins, that have paralytic effects cu-conotoxins block presynaptic calcium channels, a-conotoxins bind to nicotinic ACh receptors in muscle, p-contoxins bind to muscle sodium channels, K-conotoxins may affect potassium channels. Other cone snail toxins include sleeper that induces sleep in mice, conopressin that produces scratching behaviour in mice and increases blood pressure in mammals and a larger (ca. 100 amino acid) toxin that produces convulsions in mice. 

Cone Snail Toxins as Therapeutics and Drug Leads 523... 

Conotoxins are the venoms of the marine cone snails. The >500 Conus species produce >10,000 different toxins. All are cysteine-rich peptides of 10-30 amino... 

When a cone snail envenomates its prey, the latter is invariably paralyzed. In all cases, the paralytic toxins in the venom ("conotoxins") appear to be small peptides, most commonly with 3 disulfide bonds (although conotoxins with 2 or 4 S-S bonds... 

The a -, /z-, and a-conotoxins are the best characterized of the peptides isolated from Conus venoms so far. However, a large number of other peptides are found in these venoms. These comprise both paralytic toxins to immobilize the prey of the cone snail, and other biologically active peptides which are not themselves directly paralytic. Only the briefest overview of these peptide components will be presented here. 

Cone snails have generated a remarkably wide array of toxins. A variety of data suggest that this genus may use novel mechanisms for evolving diverse cysteine-rich peptides. 

Prialt [Fig. 6] is a synthetic copy of a toxin from the Magician s cone snail. Conus magus, a mollusk from the Indo-Pacific region. This is also one of the first pharmaceuticals that demonstrate the promise that marine life, particularly invertebrates, holds for drug developers. 

The genus Conus comprises approximately five hundred species of predatory cone snails and is therefore, one of the largest, if not the largest, single genus of marine animals alive. Each species of snail produces a unique venom with between 50 and 200 components. These sulfur-rich peptides or conotoxins are neuropharmacologically active and modulate ion channel function [235]. Any attempt to deal with these toxins within this review would not be feasible and the reader is referred to other excellent reviews on the subject [235,236]. 

Predatory cone snails produce a variety of polypeptide toxins... 

Bacteria, protozoa, and venomous animals synthesize numerous toxins that are used to kill their prey or to defend themselves. Sea anemones, jellyfish, cone snails, insects, spiders, scorpions, and snakes all make potent and highly specific neurotoxins. Plants form a host of alkaloids and other specialized products, some of which are specifically neurotoxic and able to deter predators. More than 500 species of marine cone snails of the genus Conus synthesize a vast array of polypeptide toxins (conotoxins), 487-489 some with unusual posttranslational modifications.490 491 The slow-moving snails are voracious predators that use their toxins, which they inject with a disposible harpoonlike tooth,492 to paralyze fish, molluscs, or worms.493... 

Aga IVA and ro-conotoxin GVIA are standard tools in elucidating the roles of P/Q-type and N-type calcium channels in synaptic transmission. In many types of synapses, application of either toxin may mediate moderate inhibition of neurotransmitter release, whereas co-application of both blockers may almost abolish synaptic transmission due to the nonlinear dependence of synaptic release on intracellular calcium concentration. On a final note, we should add that there are many other species of cone snails and spiders that produce active toxins which selectivity inhibit specific calcium channel subtypes (for example, co-conotoxins GVIB, GVIC, GVIIA, SVIA, SVIB), and it is likely that many more remain to be discovered (Olivera et al. 1994). 

Cone snails, Conus spp., have been investigated because of their production of conotoxin peptides. From an evolutionary standpoint, the production of conotoxins is quite interesting due to their wide range of neurophysiological activities. The conotoxins are small peptides, 10-30 amino acids, with conformations constrained by multiple disulfide bonds that target a number of receptors in vertebrate and invertebrate nervous systems. Cone snails use these toxins to immobilize prey, which allows the relatively slow-moving cone snails to feed on fish and worms. The wide variety of conotoxins isolated and the hypervariability within peptide sequences has led some to hypothesize a combinatorial biosynthetic approach for the production of conotoxins.116117... 

The toxins identified from cone snails, nemerteans, cephalopod molluscs, etc. undoubtedly play some role in prey capture, but their importance relative to other predatory behaviors is generally unknown. For some predators, toxins may serve as a secondary rather than primary mode of... 

Nicotinic acetylcholine Conus toxins Cone snails, Conus sp. Pain22... 

NMR is particularly suitable for the study of peptidic toxins because these molecules are typically small in size (less than 50 amino acids), are usually highly soluble and very often have well-defined structures stabilised by disulphide bonds, which predispose them to have excellent dispersion in their NMR spectra. Indeed, small disulphide-rich peptides are perhaps the one area of structural biology where NMR dominates over X-ray crystallography as the preferred structural technique. The Protein Data Bank (PDB), for example, shows that of the approximately 50,000 structures deposited, less than 20% have been determined by NMR, but if the analysis is done over peptides smaller than 50 amino acids then the proportion of NMR structures is approximately 90%. An example of the important role of NMR in structure determination of peptide toxins involves those from marine cone snails known as conotoxins. Of the 125 conotoxin structures... 

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