Cobratoxin
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 Space filling diagram
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3D model (JSmol)
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PubChem CID
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| Properties | |
| C277H443N97O98S8 | |
| Molar mass | 6956.65 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Sources
[edit]Structure
[edit]Stabilization of the major loop occurs through
The first loop is stabilized because of one
The tail of the
In conclusion, the whole is held together by disulfide bonds and the loops are kept stable by
Available forms
[edit]Bioinformatics and reactivity
[edit]The sequence of
The venom has different aminoacids that are able to bind reactively to the acetylcholine receptors. These receptors can bind different ligands like acetylcholine, nicotine and cobratoxin. Lysine, K at position 23 binds selectively to Torpedo AChR (Acetylcholine receptor). The aminoacids that bind to both neuronal and Torpedo AChRs are tryptophan at position 25, aspartic acid at 27, phenylalanine at 29, arginine at 33 and 36 and phenylalanine at 65. The aminoacids responsible for the binding to alpha-7 AChR are cysteine at 26 and 30, alanine at 28 and lysine at positions 35 and 49.[3]
Mode of action
[edit]nAChRs can obtain their open conformation by a twist-like motion as seen in figure X. But this opening would only last up to 3 ms, which is too short for initiating an ion-flux. When acetylcholine binds to the receptor it remains in the open conformation for a longer period which is sufficient to cause the ion-flux. When a complex was formed with an
Cobratoxin binds to the ligand-binding pocket between the
Indications
[edit]Indications for the bite of a cobra, in this case the Naja atra (Chinese cobra) are the darkening of the bite wound and pain and swelling of the area around it. Necrosis is a very severe result of the snake bite, and can keep harming the victim for years after the attack.[8] Of course the Chinese cobra is only one of the snakes that produce cobratoxin, but the other snakes cause similar indications.
Effects
[edit]The cobratoxin of the Thailand cobra belongs to the neurotoxins. An important property of neurotoxins is that they are not usually able to cross the blood-brain barrier. Instead of this, they block the nerve transmission in the body.
Toxicity
[edit]The Naja Kaouthia venom is a member of the snake three-finger toxin family in the subfamily type II alpha-neurotoxin. The lethal dose (LD50) of
Antitoxin and vaccines
[edit]In the last few years there are some new developments to create an antitoxin or a vaccine for the toxic snake bites.
Genetic vaccine
[edit]In 2005 a genetic vaccine for cobratoxin was developed which encodes for a non-toxic cobratoxin variant. To develop this non-toxic component, some alterations were made in the cDNA for the cobratoxin. Two residues, critical for binding to the nicotinic acetylcholine receptors, were substituted (Asp27 to Arg and Arg33 to Gly).This created protein has the same 3D-structure as the original toxin but leads also to protective immunity. This synthesized vaccine could protect a victim against a dangerous snake venom. Because of these promising results, the creation of a global health program must be considered which can save people who are at risk of a snakebite.[10]
Rediocides A and G
[edit]Rediocides A and G are found to be a possible antitoxin for
Applications in biomedicine
[edit]Although cobratoxin is a relatively toxic and dangerous poison it also has a beneficial side. It is a natural and biological venom and its components certainly have a potential therapeutic value which is useful for the biomedicine.[12]
Painkiller
[edit]In 2011, an investigation showed that cobratoxin could inhibit nociception, the sensation of pain. During this investigation inflammatory pain was induced on rats using formalin. The results showed that cobratoxin exhibited a dose-dependent pain-killing effect on this formalin induced pain. Apparently, when the nAChr receptors in the central nervous system gets activated it provokes anti-nociceptive effects .[13]
Multiple sclerosis
[edit]Multiple sclerosis, briefly MS, is an autoimmune disease of the central nervous system (CNS). The immune system attacks the CNS which leads to demyelination. Myelin forms a layer, the myelin sheath, around the axons and neurons. When this sheath is damaged the transport of action potentials will no longer work effectively. The cause of this disease is still unknown but there is a possible chance that the disease is induced or worsened by viral infection. It appears to be that cobra venoms such as cobratoxin have an ‘antiviral, immunomodulatory and a neuromodulatory activity’. These properties make it a suitable candidate for a study in subjects with MS and contribute to the disease process.[citation needed]
Lung cancer
[edit]In 2009 promising results showed that the acetylcholine receptor plays an import role in developing lung cancer. Nicotine stimulates the tumor growth on our lungs.[14] By binding to this receptor it activates some pathways which will block the apoptosis. As a consequence, unregulated cell proliferation occurs. This cell proliferation caused by nicotine could be blocked by using cobratoxin. Cobratoxin blocks the acetylcholine receptor because of the high affinity.[15] Unfortunately, in 2011 this theory has been disproven and the original article was retracted for fabrication of results.[15] Mice treated with cobratoxin did not show any significant reduction in tumor growth. The conclusion of these results, in contrast with earlier results, was that the acetylcholine receptor inhibitors neither suppressed growth of the lung tumors nor prolonged the lives of the mice.[16]
References
[edit]- ^ Betzel C, Lange G, Pal GP, Wilson KS, Maelicke A, Saenger W (1991). "The refined crystal structure of alpha-cobratoxin from Naja naja siamensis at 2.4-A resolution". The Journal of Biological Chemistry. 266 (32): 21530–6. doi:10.2210/pdb2ctx/pdb. PMID 1939183.
- ^ Osipov, A. V.; Kasheverov, I. E.; Makarova, Y. V.; Starkov, V. G.; Vorontsova, O. V.; Ziganshin, R. Kh.; Andreeva, T. V.; Serebryakova, M. V.; Benoit, A.; Hogg, R. C.; Bertrand, D.; Tsetlin, V. I.; Utkin, Y. N. (2008). "Naturally occurring disulfide-bound dimers of three-fingered toxins: a paradigm for biological activity diversification". The Journal of Biological Chemistry. 283 (21): 14571–80. doi:10.1074/jbc.M802085200. PMID 18381281.
- ^ Protein Data Bank from: http://www.rcsb.org/pdb/home/home.do[full citation needed][permanent dead link]
- ^ a b Samson AO, Levitt M (2008). "Inhibition mechanism of the acetylcholine receptor by alpha-neurotoxins as revealed by normal-mode dynamics". Biochemistry. 47 (13): 4065–70. doi:10.1021/bi702272j. PMC 2750825. PMID 18327915.
- ^ Whiteaker P, Christensen S, Yoshikami D, Dowell C, Watkins M, Gulyas J, Rivier J, Olivera BM, McIntosh JM (2007). "Discovery, synthesis, and structure activity of a highly selective alpha7 nicotinic acetylcholine receptor antagonist". Biochemistry. 46 (22): 6628–38. doi:10.1021/bi7004202. PMID 17497892.
- ^ Chen et al. 2006
- ^ Hue et al. 2007
- ^ Association, A.M. and B.M. Association, Medical Journal of Australia1992: Australasian Medical Publishing Company.[page needed]
- ^ a b Del Brutto OH, Del Brutto VJ (2012). "Neurological complications of venomous snake bites: a review". Acta Neurologica Scandinavica. 125 (6): 363–72. doi:10.1111/j.1600-0404.2011.01593.x. PMID 21999367. S2CID 135451181.
- ^ Pergolizzi RG, Dragos R, Ropper AE, Menez A, Crystal RG (2005). "Protective immunity against alpha-cobratoxin following a single administration of a genetic vaccine encoding a non-toxic cobratoxin variant". Human Gene Therapy. 16 (3): 292–8. doi:10.1089/hum.2005.16.292. PMID 15812224.
- ^ Utsintong M, Kaewnoi A, Leelamanit W, Olson AJ, Vajragupta O (2009). "Rediocides A and G as potential antitoxins against cobra venom". Chemistry & Biodiversity. 6 (9): 1404–14. doi:10.1002/cbdv.200800204. PMID 19774596. S2CID 198838.
- ^ Koh DC, Armugam A, Jeyaseelan K (2006). "Snake venom components and their applications in biomedicine". Cellular and Molecular Life Sciences. 63 (24): 3030–41. doi:10.1007/s00018-006-6315-0. PMC 11135979. PMID 17103111. S2CID 9953058.
- ^ Shi GN, Liu YL, Lin HM, Yang SL, Feng YL, Reid PF, Qin ZH (2011). "Involvement of cholinergic system in suppression of formalin-induced inflammatory pain by cobratoxin". Acta Pharmacologica Sinica. 32 (10): 1233–8. doi:10.1038/aps.2011.65. PMC 4010082. PMID 21841815.
- ^ Warren, Graham W.; Singh, Anurag K. (2013-01-31). "Nicotine and lung cancer". Journal of Carcinogenesis. 12: 1. doi:10.4103/1477-3163.106680. ISSN 0974-6773. PMC 3622363. PMID 23599683.
- ^ a b Paleari L, Catassi A, Ciarlo M, Cavalieri Z, Bruzzo C, Servent D, Cesario A, Chessa L, Cilli M, Piccardi F, Granone P, Russo P (2008). "Role of alpha7-nicotinic acetylcholine receptor in human non-small cell lung cancer proliferation". Cell Proliferation. 41 (6): 936–59. doi:10.1111/j.1365-2184.2008.00566.x. PMC 9531952. PMID 19040571. S2CID 22484974. (Retracted, see doi:10.1111/cpr.12379, Retraction Watch)
- ^ Alama A, Bruzzo C, Cavalieri Z, Forlani A, Utkin Y, Casciano I, Romani M (2011). "Inhibition of the nicotinic acetylcholine receptors by cobra venom
α -neurotoxins: is there a perspective in lung cancer treatment?". PLOS ONE. 6 (6): e20695. Bibcode:2011PLoSO...620695A. doi:10.1371/journal.pone.0020695. PMC 3113800. PMID 21695184.
Works cited
[edit]- Chen, Zhi-xin; Zhang, Hui-ling; Gu, Zhen-lun; Chen, Bo-wen; Han, Rong; Reid, Paul F; Raymond, Laurence N; Qin, Zheng-hong (April 2006). "A long-form alpha-neurotoxin from cobra venom produces potent opioid-independent analgesia". Acta Pharmacologica Sinica. 27 (4): 402–408. doi:10.1111/j.1745-7254.2006.00293.x. PMID 16539838. S2CID 36098764.
- Hue, Bernard; Buckingham, Steven D.; Buckingham, David; Sattelle, David B. (27 August 2007). "Actions of snake neurotoxins on an insect nicotinic cholinergic synapse". Invertebrate Neuroscience. 7 (3): 173–178. doi:10.1007/s10158-007-0053-3. PMID 17710455. S2CID 31599093.
External links
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Media related to Cobratoxin at Wikimedia Commons
