Open Access Articles- Top Results for Saxitoxin


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Skeletal formula

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IUPAC name
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This page is a soft redirect. Properties

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Saxitoxin (STX) is the best-known paralytic shellfish toxin (PST). Ingestion of saxitoxin (usually through shellfish contaminated by toxic algal blooms) is responsible for the human illness known as paralytic shellfish poisoning (PSP).

The term saxitoxin originates from the species name of the butter clam (Saxidomus giganteus) in which it was first recognized. But, the term saxitoxin can also refer to the entire suite of related neurotoxins (known collectively as "saxitoxins") produced by these microorganisms, which include pure saxitoxin (STX), neosaxitoxin (NSTX), gonyautoxins (GTX) and decarbamoylsaxitoxin (dcSTX).

Saxitoxin has a large environmental and economic impact, as its detection in shellfish such as mussels, clams and scallops frequently leads to closures of commercial and recreational shellfish harvesting, especially in California, Oregon, Washington, and New England.

Source in nature

STX is a neurotoxin naturally produced by certain species of marine dinoflagellates (Alexandrium sp., Gymnodinium sp., Pyrodinium sp.) and cyanobacteria (Anabaena sp., some Aphanizomenon spp., Cylindrospermopsis sp., Lyngbya sp., Planktothrix sp.)[1][2]

STX has been found in at least 12 marine puffer fish species in Asia and one freshwater fish tilapia in Brazil.[3] However, the ultimate source of STX is often still uncertain. In the United States, paralytic shellfish poisoning is limited to New England and the West Coast. The dinoflagellate Pyrodinium bahamense is the source of STX found in Florida.[4][5] Recent research shows the detection of STX in the skin, muscle, viscera, and gonads of “Indian River Lagoon” southern puffer fish, with the highest concentration (22,104 μg STX eq/100 g tissue) measured in the ovaries. Even after a year of captivity, the skin mucus remained highly toxic.[6] The various concentrations in puffer fish from the United States are similar to those found in the Philippines, Thailand,[5] Japan,[7] Japan,[5] and South American countries.[8]

Mechanism of action

File:Neurotoxin Sodium Channel Binding Sites.png
This is a diagram of the membrane topology of a voltage gated sodium channel protein. Binding sites for different neurotoxins are indicated by color. Saxitoxin is denoted by red.
See also: Sodium channel

Saxitoxin is a neurotoxin that acts as a selective sodium channel blocker.[9] One of the most potent natural toxins known to man, it acts on the voltage-gated sodium channels of neurons, preventing normal cellular function and leading to paralysis.

The voltage-gated sodium channel is essential for normal neuronal functioning. They exist as integral membrane proteins interspersed along the axon of a neuron and possess four domains that span the cell membrane. Opening of the voltage-gated sodium channel occurs when there is a change in voltage or some ligand binds in the right way. It is of foremost importance for these sodium channels to function properly, as they are essential for the propagation of an action potential. Without this ability, the nerve cell becomes unable to transmit signals and the region of the body that it innervates is cut off from the nervous system. This may lead to paralysis of the affected region, as in the case of saxitoxin.

Saxitoxin binds reversibly to the sodium channel. It binds directly in the pore of the channel protein, occluding the opening, and preventing the flow of sodium ions through the membrane. This leads to the nervous shutdown explained above.


Although STX biosynthesis seems complex, organisms from two different kingdoms, species of marine dinoflagellates and freshwater cyanobacteria, are capable of producing these toxins. While the prevailing theory of production in dinoflagellates was through symbiotic mutualism with cyanobacteria, evidence has emerged suggesting that dinoflagellates, themselves, also possess the genes required for saxitoxin synthesis.[10]

Saxitoxin synthesis is the first non-terpene alkaloid pathway described for bacteria, though the exact mechanism of saxitoxin biosynthesis is still at heart a theoretical model. The precise mechanism of how substrates bind to enzymes is still unknown, and genes involved in the biosynthesis of saxitoxin are either putative or have only recently been identified.[10][11]

Two biosyntheses have been proposed in the past. Earlier versions differ from a more recent proposal by Kellmann, based on both biosynthetic considerations as well as genetic evidence not available at the time of the first proposal. The more recent model describes a STX gene cluster (sxt) used to obtain a more favorable reaction. The most recent reaction sequence of Sxt in cyanobacteria[11] is as follows. Refer to the diagram for a detailed biosynthesis and intermediate structures.

  1. It begins with the loading of the acyl carrier protein (ACP) with acetate from acetyl-CoA, yielding intermediate 1.
  2. This is followed by SxtA-catalyzed methylation of acetyl-ACP, which is then converted to propionyl-ACP, yielding intermediate 2.
  3. Later, another SxtA performs a Claisen condensation reaction between propionyl-ACP and arginine producing intermediate 4 and intermediate 3.
  4. SxtG transfers an amidino group from an arginine to the α-amino group of intermediate 4 producing intermediate 5.
  5. Intermediate 5 then undergoes retroaldol-like condensation by SxtBC, producing intermediate 6.
  6. SxtD adds a double bond between C-1 and C-5 of intermediate 6, which gives rise to the 1,2-H shift between C-5 and C-6 in intermediate 7.
  7. SxtS performs an epoxidation of the double bond yielding intermediate 8, and then an opening of the epoxide to an aldehyde, forming intermediate 9.
  8. SxtU reduces the terminal aldehyde group of the STX intermediate 9, thus forming intermediate 10.
  9. SxtIJK catalyzes the transfer of a carbamoyl group to the free hydroxyl group on intermediate 10, forming intermediate 11.
  10. SxtH and SxtT, in conjunction with SxtV and the SxtW gene cluster, perform a similar function which is the consecutive hydroxylation of C-12, thus producing saxitoxin and terminating the STX biosynthetic pathway.

Illness and poisoning


STX is highly toxic to guinea pigs, fatal at only 5 μg/kg when injected intramuscularly. The lethal doses for mice are very similar with varying administration routes: t i.p. (LD50 = 10 μg/kg), i.v. (LD50 = 3.4 μg/kg) or p.o. (LD50 = 263 μg/kg). The oral LD50 for humans is 5.7 μg/kg, therefore approximately 0.57 mg of saxitoxin is lethal if ingested and the lethal dose by injection is about ten times lower (approximately 0.6 μg). The human inhalation toxicity of aerosolized saxitoxin is estimated to be 5 mg·min/m³. Saxitoxin can enter the body via open wounds and a lethal dose of 50 μg/person by this route has been suggested.[12]

Illness in humans

The human illness associated with ingestion of harmful levels of saxitoxin is known as paralytic shellfish poisoning, or PSP, and saxitoxin and its derivatives are often referred to as "PSP toxins".[1]

The medical and ecological importance of saxitoxin lies mainly in effects of harmful algal blooms on shellfish and certain finfish which can concentrate the toxin, making it available both for human consumption as well as by various marine organisms. The blocking of neuronal sodium channels which occurs in PSP produces a flaccid paralysis that leaves its victim calm and conscious through the progression of symptoms. Death often occurs from respiratory failure. PSP toxins have been implicated in various marine animal mortalities involving trophic transfer of the toxin from its algal source up the food web to higher predators.

There are some reports on reversal of lethal effects of saxitoxin using 4-aminopyridine,[13][14][15] but there are no studies on human subjects.

Military interest

Saxitoxin, by virtue of its extremely low LD50, readily lends itself to weaponization. In the past, it was considered for military use by the United States and was developed as a chemical weapon by the US military.[16] It is known that saxitoxin was developed for both overt military use as well as for covert purposes by the CIA.[17] Among weapons stockpiles were M1 munitions that contained either saxitoxin or botulinum toxin or a mixture of both.[18] On the other hand, the CIA is known to have issued a small dose of saxitoxin to U-2 spy plane pilot Francis Gary Powers in the form of a small injection hidden within a silver dollar, for use in the event of his capture and detainment.[17][18]

After the 1969 outlaw of biological warfare by president Nixon, the US stockpiles of saxitoxin were destroyed, and development of saxitoxin as a military weapon ceased.[19] There was, however, an incident in 1975, when the CIA admitted to congress that they had been keeping a secret stockpile of saxitoxin and snake venom, against Nixon’s orders. The saxitoxin was distributed to researchers and this stockpile was also dismantled.[17]

It is listed in schedule 1 of the Chemical Weapons Convention. The United States military isolated saxitoxin and assigned it the chemical weapon designation TZ.

See also


  1. ^ a b Clark R. F., Williams S. R., Nordt S. P., Manoguerra A. S. (1999). "A review of selected seafood poisonings". Undersea Hyperb Med 26 (3): 175–84. PMID 10485519. Retrieved 2008-08-12. 
  2. ^ Landsberg, Jan H. (2002). "The Effects of Harmful Algal Blooms on Aquatic Organisms". Reviews in Fisheries Science 10 (2): 113–390. doi:10.1080/20026491051695. 
  3. ^ Galvão, J. A.; Oetterer, M.; Bittencourt-Oliveira Mdo, M. D. C.; Gouvêa-Barros, S.; Hiller, S.; Erler, K.; Luckas, B.; Pinto, E.; Kujbida, P. (2009). "Saxitoxins accumulation by freshwater tilapia (Oreochromis niloticus) for human consumption". Toxicon 54 (6): 891–894. PMID 19560484. doi:10.1016/j.toxicon.2009.06.021. 
  4. ^ Smith, E. A.; Grant, F.; Ferguson, C. M. J.; Gallacher, S. (2001). "Biotransformations of Paralytic Shellfish Toxins by Bacteria Isolated from Bivalve Molluscs". Applied and Environmental Microbiology 67 (5): 2345–2353. PMC 92876. PMID 11319121. doi:10.1128/AEM.67.5.2345-2353.2001. 
  5. ^ a b c Sato, S.; Kodama, M.; Ogata, T.; Saitanu, K.; Furuya, M.; Hirayama, K.; Kakinuma, K. (1997). "Saxitoxin as a toxic principle of a freshwater puffer, Tetraodon fangi, in Thailand". Toxicon 35 (1): 137–140. PMID 9028016. doi:10.1016/S0041-0101(96)00003-7. 
  6. ^ Landsberg, J. H.; Hall, S.; Johannessen, J. N.; White, K. D.; Conrad, S. M.; Abbott, J. P.; Flewelling, L. J.; Richardson, R. W.; Dickey, R. W.; Jester, Edward L.E.; Etheridge, Stacey M.; Deeds, Jonathan R.; Van Dolah, Frances M.; Leighfield, Tod A.; Zou, Yinglin; Beaudry, Clarke G.; Benner, Ronald A.; Rogers, Patricia L.; Scott, Paula S.; Kawabata, Kenji; Wolny, Jennifer L.; Steidinger, Karen A. (2006). "Saxitoxin Puffer Fish Poisoning in the United States, with the First Report of Pyrodinium bahamense as the Putative Toxin Source". Environmental Health Perspectives 114 (10): 1502–1507. PMC 1626430. PMID 17035133. doi:10.1289/ehp.8998. 
  7. ^ Deeds, J. R.; Landsberg, J. H.; Etheridge, S. M.; Pitcher, G. C.; Longan, S. W. (2008). "Non-Traditional Vectors for Paralytic Shellfish Poisoning". Marine Drugs 6 (2): 308–348. PMC 2525492. PMID 18728730. doi:10.3390/md6020308. 
  8. ^ Lagos, N. S.; Onodera, H.; Zagatto, P. A.; Andrinolo, D. ́O.; Azevedo, S. M. F. Q.; Oshima, Y. (1999). "The first evidence of paralytic shellfish toxins in the freshwater cyanobacterium Cylindrospermopsis raciborskii, isolated from Brazil". Toxicon 37 (10): 1359–1373. PMID 10414862. doi:10.1016/S0041-0101(99)00080-X. 
  9. ^ Huot, R. I.; Armstrong, D. L.; Chanh, T. C. (June 1989). "Protection against nerve toxicity by monoclonal antibodies to the sodium channel blocker tetrodotoxin". Journal of Clinical Investigation 83 (6): 1821–1826. PMC 303901. PMID 2542373. doi:10.1172/JCI114087. 
  10. ^ a b Stüken, Anke; Orr, Russell; Kellmann, Ralf; Murray, Shauna; Neilan, Brett; Jakobsen, Kjetill (18 May 2011). "Discovery of Nuclear-Encoded Genes for the Neurotoxin Saxitoxin in Dinoflagellates". PLoS One 6 (5): e20096. doi:10.1371/journal.pone.0020096. Retrieved 1 May 2015. 
  11. ^ a b Kellmann, R.; Mihali, T. K.; Jeon, Y. J.; Pickford, R.; Pomati, F.; Neilan, B. A. (2008). "Biosynthetic Intermediate Analysis and Functional Homology Reveal a Saxitoxin Gene Cluster in Cyanobacteria". Applied and Environmental Microbiology 74 (13): 4044–4053. PMC 2446512. PMID 18487408. doi:10.1128/AEM.00353-08. 
  12. ^ Patocka J; Stredav L (April 23, 2002). Price, Richard, ed. "Brief Review of Natural Nonprotein Neurotoxins". ASA Newsletter (Applied Science and Analysis inc.) 02–2 (89): 16–23. ISSN 1057-9419. Retrieved 26 May 2012. 
  13. ^ Template:Cite pmid/9643470
  14. ^ Chang, F. C.; Spriggs, D. L.; Benton, B. J.; Keller, S. A.; Capacio, B. R. (1997). "4-Aminopyridine reverses saxitoxin (STX)- and tetrodotoxin (TTX)-induced cardiorespiratory depression in chronically instrumented guinea pigs". Fundamental and applied toxicology : official journal of the Society of Toxicology 38 (1): 75–88. PMID 9268607. doi:10.1006/faat.1997.2328. 
  15. ^ Template:Cite pmid/8917674
  16. ^ Stewart, Charles Edward (2006). Weapons of Mass Casualties and Terrorism Response Handbook. Jones & Bartlett Learning. p. 175. ISBN 978-0-7637-2425-2. Retrieved 4 May 2015. 
  17. ^ a b c Unauthorized Storage of Toxic Agents. Church Committee Reports 1. The Assassination Archives and Research Center (AARC). 1975–1976. p. 7. 
  18. ^ a b Wheelis, Mark; Rozsa, Lajós; Dando, Malcolm (2006). Deadly Cultures: Biological Weapons since 1945. President and Fellows of Harvard College. p. 39. ISBN 0-674-01699-8. Retrieved 4 May 2015. 
  19. ^ Mauroni, Albert J. (2000). America's Struggle with Chemical-biological Warfare. 88 Post Road West, Westport, CT 06881: Praeger Publishers. p. 50. ISBN 0-275-96756-5. Retrieved 4 May 2015. 

External links

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