Toxins cardiotoxins

A second group of myotoxic toxins, found almost exclusively in the venoms of cobras, are the cytotoxins (often called cobratoxins, cytolysins, cardiotoxins, or direct lytic factors). These, rather than phospholipases, are almost certainly the primary cause of muscle damage following bites by cobras. Their mechanism of action is not properly known, but it is certainly the case that their action is potentiated by the presence of phospholipases in the venom, even if the phospholipases concerned are not, themselves, myotoxic. The cytotoxins of cobra venom possess no hydrolytic activity of any kind. 

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. 

Dendrobatidae Phyllobates aurotaenia Cardiotoxin Neuro toxin Batrachotoxin Homobatrachotoxin... 

Two recent publications provide new and provocative input to this dialogue. One of these involved a series of appearances of a reddish substance on the East Coast called Chinese Love Stone, Black Stone, Rock Hard or Stud 100, being sold as aphrodisiacs. They were to be moistened and rubbed on the genitals, but as might be expected, quite a few were eaten and eventually smoked. They contained steroidal toxins, and were possibly related to some frog origins, but they were claimed to be bufotenine and indeed contained bufotenine in addition to several cardiotoxins as well as 5-MeO-DMT. 

Various types of proteins have been purified using hydrophobic interaction chromatography including alkaline phophatase, estrogen receptors, isolectins, strepavidin, calmodulin, epoxide hydrolase, proteoglycans, hemoglobins, and snake venom toxins (46). In the case of cobra venom toxins, the order of elution of the six cardiotoxins supports the hypothesis that the mechanism of action is related to hydrophobic interactions with the phospholipids in the membrane. 

The effect of toxins such as melittin (from the honey-bee venom), myotoxin a, and cardiotoxin (from the snake venom) was investigated by vibrational spectroscopy (Pezolet et al., 1982 Faucon et ah, 1983 Liddle and Tu, 1985 Lafleur et ah, 1987). Monitoring the Raman intensity ratio I(1060)/I(1080) indicated that the lipid/melittin assemblies in DPPC are characterized by a high conformational order, little intermolecular chain-chain interaction, and a low cooperativity of the gel-like liquid crystalline phase transition. The effect of ricin, a toxic lectin, on DPPC and DPPC-cerebroside mixtures was studied by Raman and IR spectroscopy. It was suggested that ricin mainly interacts with the interfacial domains of the bilayers (Picquart et ah, 1989). 

These venoms are a rapid-acting mixture of various types of toxins including neurotoxins, cardiotoxins, and cytotoxins. 

The heart poisons or cardiotoxins are, in reality, general muscle poisons. However their effect on the muscle of the heart is by far the most important in terms of killing the snake s prey or attacker. These incredibly potent toxins bind to specific biochemical sites on the surface of muscle cells causing depolarisation. The muscle cell works in a manner akin to neurones in that it transmits information, to initiate a contraction, by exchanging + and - ions across its cell... 

There is very little known about the haemolytic toxins, indeed it is often difficult to distinguish them from the cardiotoxins, because the cardiotoxins often also have haemolytic properties. 

Cardiotoxins in the widest sense, substances which, in toxic doses, cause heart damage and may lead to heart stoppage. They may interfere with the generation or conduction of stimuli or with the heart s own blood supply, or they may directly attack the heart muscle. In the narrower sense, they include the cardiac glycosides and their aglycones from plants, and a group of toad toxins. 

Important toxins are cobramine A and B from cobra toxin and crotactine and crotamine from crotox-in, the toxin of the North American rattlesnake. The toxic proteins are classified according to their mode of action cardiotoxins, neuFotoxins and protease inhibitors (with inhibitory activity toward chymotrypsin and trypsin). Cardiotoxins (heart muscle poisons) cause an irreversible depolarization of the cell membranes of heart muscle and nerve cells. Neurotoxins (nerve poisons) show curare-like activity they prevent neuromuscular transmission by blocking the receptors for the transmitters at the synapses of autonomic nerve endings and at the motor end plate of skeletal muscle. Protease inhibitors inhibit acetylcholine esterase and similar enzymes involved in nerve transmission. 

Fasciculins belong to the structural family of threefingered toxins from Elapidae snake venoms, which include the a-neurotoxins that block the nAChR and the cardiotoxins that interact with cell membranes. The features unique to the known primary and tertiary structures of the fasciculin molecule were analyzed by Flarald et al. (1995). Loop I contains an arginine at position 11, which is found only in the fasciculins and could form a pivotal anchoring point to AChE. Loop II contains five cationic residues near its tip, which are partly charge-compensated by anionic side chains in loop III. 

Some snake venoms are more toxic than others because the type and amount of toxic components present in their venoms are different. Usually neurotoxins are most powerful. Cardiotoxins, cytotoxins, hemorrhagic toxins, and myotoxins are also highly toxic but less toxic than neurotoxins. 

Figure 3. Examples of neurotoxins (A, C) and a cardiotoxin (B). (A) Primary structure of lapemis toxin, a short-chain postsynaptic neurotoxin. (B) Cardiotoxin from Naja naja venom. (C) Toxin B from Naja naja venom.

The crystalline structure of fasciculin 2 indicates that the toxin is structurally related to both cardiotoxin and a-neurotoxins (le Du et al., 1989). The crystals are tetragonal, with unit cell dimensions of a = 48.9 A and c = 82.0 A and with the space group of P41212 or P43212. There are 16 molecules in the unit cell. Fasciculin 1 was also examined by x-ray crystallography. The unit cell values for fasciculin 1 are a = 40.4 A and c = 81.1 A, with the space group P4(l)2(l)2 or P4(3)2(l)2. It is estimated that there is one molecule in the asymmetric unit (Menez and Ducruix, 1990). 

The Taiwan cobra (Naja naja atm) is a rich source for the cardiotoxins (37). To date six isoforms have been isolated from this source (38). The isoforms are numbered on column chromatographic profiles (39). Of the six isoforms, cardiotoxin III (CTX III) is the major fraction. It constitutes 50 - 60% of the total dry weight of the cardiotoxin isoforms and hence the best characterized (of the toxin isoforms) from this source (Naja naja atm) (40). 

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