Saxitoxin

Last updated
Saxitoxin
Saxitoxin neutral.svg
Saxitoxin-3D-balls.png
Saxitoxin-3D-spacefill.png
Names
IUPAC name
[(3aS,4R,10aS)-10,10-dihydroxy-2,6-diiminooctahydro-1H,8H-pyrrolo[1,2-c]purin-4-yl]methyl carbamate
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.160.395 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C10H17N7O4/c11-6-15-5-4(3-21-8(13)18)14-7(12)17-2-1-9(19,20)10(5,17)16-6/h4-5,19-20H,1-3H2,(H2,12,14)(H2,13,18)(H3,11,15,16)/t4-,5-,10-/m0/s1 X mark.svgN
    Key: RPQXVSUAYFXFJA-HGRQIUPRSA-N X mark.svgN
  • InChI=1/C10H17N7O4/c11-6-15-5-4(3-21-8(13)18)14-7(12)17-2-1-9(19,20)10(5,17)16-6/h4-5,19-20H,1-3H2,(H2,12,14)(H2,13,18)(H3,11,15,16)/t4-,5-,10-/m0/s1
    Key: RPQXVSUAYFXFJA-HGRQIUPRBO
  • O=C(OC[C@@H]2/N=C(/N)N3[C@]1(/N=C(\N[C@H]12)N)C(O)(O)CC3)N
Properties
C10H17N7O4
Molar mass 299.291 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Saxitoxin (STX) is a potent neurotoxin and the best-known paralytic shellfish toxin (PST). Ingestion of saxitoxin by humans, usually by consumption of shellfish contaminated by toxic algal blooms, is responsible for the illness known as paralytic shellfish poisoning (PSP).

Contents

The term saxitoxin originates from the genus name of the butter clam ( Saxidomus ) from which it was first isolated. But the term saxitoxin can also refer to the entire suite of more than 50 structurally related neurotoxins (known collectively as "saxitoxins") produced by protists, algae and cyanobacteria which includes saxitoxin itself (STX), neosaxitoxin (NSTX), gonyautoxins (GTX) and decarbamoylsaxitoxin (dcSTX).

Saxitoxin has a large environmental and economic impact, as its presence in bivalve shellfish such as mussels, clams, oysters and scallops frequently leads to bans on commercial and recreational shellfish harvesting in many temperate coastal waters around the world including the Northeastern and Western United States, Western Europe, East Asia, Australia, New Zealand, and South Africa. In the United States, paralytic shellfish poisoning has occurred in California, Oregon, Washington, Alaska, and New England.

Source in nature

Saxitoxin is a neurotoxin naturally produced by certain species of marine dinoflagellates (Alexandrium sp., Gymnodinium sp., Pyrodinium sp.) and freshwater cyanobacteria ( Dolichospermum cicinale sp., some Aphanizomenon spp., Cylindrospermopsis sp., Lyngbya sp., Planktothrix sp.) [1] [2] Saxitoxin accumulates in "planktivorous invertebrates, including mollusks (bivalves and gastropods), crustaceans, and echinoderms". [3]

Saxitoxin has also been found in at least twelve marine puffer fish species in Asia and one freshwater fish tilapia in Brazil. [4] The ultimate source of STX is often still uncertain. The dinoflagellate Pyrodinium bahamense is the source of STX found in Florida. [5] [6] 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, Landsberg et al. found the skin mucus remained highly toxic. [7] The concentrations in puffer fish from the United States are similar to those found in the Philippines, Thailand, [6] Japan, [6] [8] and South American countries. [9] Puffer fish also accumulate a structurally distinct toxin, tetrodotoxin. [10]

Structure and synthesis

Saxitoxin dihydrochloride is an amorphous hygroscopic solid, but X-ray crystallography of crystalline derivatives enabled the structure of saxitoxin to be determined. [11] [12] Oxidation of saxitoxin generates a highly fluorescent purine derivative which has been utilized to detect its presence. [13]

Several total syntheses of saxitoxin have been accomplished. [14] [15] [16]

Mechanism of action

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. Neurotoxin Sodium Channel Binding Sites.png
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.

Saxitoxin is a neurotoxin that acts as a selective, reversible, voltage-gated sodium channel blocker. [17] [18] One of the most potent known natural toxins, it acts on the voltage-gated sodium channels of neurons, preventing normal cellular function and leading to paralysis. [3]

The voltage-gated sodium channel is essential for normal neuronal functioning. It exists as integral membrane proteins interspersed along the axon of a neuron and possessing 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 enervates is cut off from the nervous system. This may lead to paralysis of the affected region, as in the case of saxitoxin. [3]

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 described above. [3]

Biosynthesis

Although the biosynthesis of saxitoxin seems complex, organisms from two different kingdoms, indeed two different domains, 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. [19]

Saxitoxin biosynthesis is the first non-terpene alkaloid pathway described for bacteria, though the exact mechanism of saxitoxin biosynthesis is still essentially 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. [19] [20]

Two biosyntheses have been proposed in the past. Earlier versions differ from a more recent proposal by Kellmann, et al. 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 [20] is as follows. Refer to the diagram for a detailed biosynthesis and intermediate structures.

Biosynthesis Saxitoxin Biosynthesis.PNG
Biosynthesis
  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

Toxicology

Saxitoxin is highly toxic to guinea pigs, fatal at only 5 μg/kg when injected intramuscularly. The lethal doses (LD50) for mice are very similar with varying administration routes: i.v. is 3.4 μg/kg, i.p. is 10 μg/kg and p.o. is 263 μg/kg. The oral LD50 for humans is 5.7 μg/kg, therefore approximately 0.57 mg of saxitoxin (1/8th of a medium-sized grain of sand) is lethal if ingested and the lethal dose by injection is about one-tenth of that (approximately 0.6 μg/kg). 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. [21]

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 environmental importance of saxitoxin derives from the consumption of contaminated shellfish and certain finfish which can concentrate the toxin from dinoflagellates or cyanobacteria. 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 chain to higher predators. [3]

Studies in animals have shown that the lethal effects of saxitoxin can be reversed with 4-aminopyridine, [22] [23] [24] but there are no studies on human subjects. As with any paralytic agent, where the acute concern is respiratory failure, mouth-to-mouth resuscitation or artificial ventilation of any means will keep a poisoned victim alive until antidote is administered or the poison wears off. [25]

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. [26] It is known that saxitoxin was developed for both overt military use as well as for covert purposes by the CIA. [27] Among weapons stockpiles were M1 munitions that contained either saxitoxin or botulinum toxin or a mixture of both. [28] 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. [27] [28]

After the 1969 ban on biological warfare by President Nixon, the US stockpiles of saxitoxin were destroyed, and development of saxitoxin as a military weapon ceased. [29] In 1975, the CIA reported to Congress that it had kept a small amount of saxitoxin and cobra venom against Nixon's orders which was then destroyed or distributed to researchers. [27]

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. [30]

See also

Related Research Articles

<span class="mw-page-title-main">Toxin</span> Naturally occurring organic poison

A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919) and is derived from the word "toxic".

<span class="mw-page-title-main">Tetrodotoxin</span> Neurotoxin

Tetrodotoxin (TTX) is a potent neurotoxin. Its name derives from Tetraodontiformes, an order that includes pufferfish, porcupinefish, ocean sunfish, and triggerfish; several of these species carry the toxin. Although tetrodotoxin was discovered in these fish, it is found in several other animals. It is also produced by certain infectious or symbiotic bacteria like Pseudoalteromonas, Pseudomonas, and Vibrio as well as other species found in symbiotic relationships with animals and plants.

<span class="mw-page-title-main">Cyanotoxin</span> Toxin produced by cyanobacteria

Cyanotoxins are toxins produced by cyanobacteria. Cyanobacteria are found almost everywhere, but particularly in lakes and in the ocean where, under high concentration of phosphorus conditions, they reproduce exponentially to form blooms. Blooming cyanobacteria can produce cyanotoxins in such concentrations that they can poison and even kill animals and humans. Cyanotoxins can also accumulate in other animals such as fish and shellfish, and cause poisonings such as shellfish poisoning.

<span class="mw-page-title-main">Palytoxin</span> Chemical compound

Palytoxin, PTX or PLTX is an intense vasoconstrictor, and is considered to be one of the most poisonous non-protein substances known, second only to maitotoxin in terms of toxicity in mice.

<span class="mw-page-title-main">Paralytic shellfish poisoning</span> Syndrome of shellfish poisoning

Paralytic shellfish poisoning (PSP) is one of the four recognized syndromes of shellfish poisoning, which share some common features and are primarily associated with bivalve mollusks. These shellfish are filter feeders and accumulate neurotoxins, chiefly saxitoxin, produced by microscopic algae, such as dinoflagellates, diatoms, and cyanobacteria. Dinoflagellates of the genus Alexandrium are the most numerous and widespread saxitoxin producers and are responsible for PSP blooms in subarctic, temperate, and tropical locations. The majority of toxic blooms have been caused by the morphospecies Alexandrium catenella, Alexandrium tamarense, Gonyaulax catenella and Alexandrium fundyense, which together comprise the A. tamarense species complex. In Asia, PSP is mostly associated with the occurrence of the species Pyrodinium bahamense.

<i>Anabaena circinalis</i> Species of bacterium

Anabaena circinalis is a species of Gram-negative, photosynthetic cyanobacteria common to freshwater environments throughout the world. Much of the scientific interest in A. circinalis owes to its production of several potentially harmful cyanotoxins, ranging in potency from irritating to lethal. Under favorable conditions for growth, A. circinalis forms large algae-like blooms, potentially harming the flora and fauna of an area.

<span class="mw-page-title-main">Anatoxin-a</span> Chemical compound

Anatoxin-a, also known as Very Fast Death Factor (VFDF), is a secondary, bicyclic amine alkaloid and cyanotoxin with acute neurotoxicity. It was first discovered in the early 1960s in Canada, and was isolated in 1972. The toxin is produced by multiple genera of cyanobacteria and has been reported in North America, South America, Central America, Europe, Africa, Asia, and Oceania. Symptoms of anatoxin-a toxicity include loss of coordination, muscular fasciculations, convulsions and death by respiratory paralysis. Its mode of action is through the nicotinic acetylcholine receptor (nAchR) where it mimics the binding of the receptor's natural ligand, acetylcholine. As such, anatoxin-a has been used for medicinal purposes to investigate diseases characterized by low acetylcholine levels. Due to its high toxicity and potential presence in drinking water, anatoxin-a poses a threat to animals, including humans. While methods for detection and water treatment exist, scientists have called for more research to improve reliability and efficacy. Anatoxin-a is not to be confused with guanitoxin, another potent cyanotoxin that has a similar mechanism of action to that of anatoxin-a and is produced by many of the same cyanobacteria genera, but is structurally unrelated.

<i>Leukoma staminea</i> Species of bivalve

Leukoma staminea, commonly known as the Pacific littleneck clam, the littleneck clam, the rock cockle, the hardshell clam, the Tomales Bay cockle, the rock clam or the ribbed carpet shell, is a species of bivalve mollusc in the family Veneridae. This species of mollusc was exploited by early humans in North America; for example, the Chumash peoples of Central California harvested these clams in Morro Bay approximately 1,000 years ago, and the distinctive shells form middens near their settlements.

Alexandrium tamarense is a species of dinoflagellates known to produce saxitoxin, a neurotoxin which causes the human illness clinically known as paralytic shellfish poisoning (PSP). Multiple species of phytoplankton are known to produce saxitoxin, including at least 10 other species from the genus Alexandrium.

<i>Canthigaster rostrata</i> Species of fish

Canthigaster rostrata, commonly known as the Caribbean sharp-nose puffer, is a pufferfish from the Western Central Atlantic. The Caribbean sharp-nose puffer is a small fish with a maximum length of 12 cm or approximately 4.7 inches. It can be encountered from the coast of South Carolina to Venezuela, including Bermuda, the Gulf of Mexico, and in the Caribbean Sea. They can live up to 10 years in the wild, females typically live longer due to aggressive male territory behavior. The Caribbean sharp-nose puffer is a highly toxic species of marine fish due to the presence of tetrodotoxin in its tissues and organs. Despite its toxicity, the sharp-nose pufferfish occasionally makes its way into the aquarium trade.

Microbial toxins are toxins produced by micro-organisms, including bacteria, fungi, protozoa, dinoflagellates, and viruses. Many microbial toxins promote infection and disease by directly damaging host tissues and by disabling the immune system. Endotoxins most commonly refer to the lipopolysaccharide (LPS) or lipooligosaccharide (LOS) that are in the outer plasma membrane of Gram-negative bacteria. The botulinum toxin, which is primarily produced by Clostridium botulinum and less frequently by other Clostridium species, is the most toxic substance known in the world. However, microbial toxins also have important uses in medical science and research. Currently, new methods of detecting bacterial toxins are being developed to better isolate and understand these toxins. Potential applications of toxin research include combating microbial virulence, the development of novel anticancer drugs and other medicines, and the use of toxins as tools in neurobiology and cellular biology.

<i>Zosimus aeneus</i> Species of crab

Zosimus aeneus, also known as the devil crab, toxic reef crab, and devil reef crab is a species of crab that lives on coral reefs in the Indo-Pacific from East Africa to Hawaii. It grows to a size of 60 mm × 90 mm and has distinctive patterns of brownish blotches on a paler background. It is potentially lethal due to the presence of the neurotoxins tetrodotoxin and saxitoxin in its flesh and shell.

<span class="mw-page-title-main">Neosaxitoxin</span> Chemical compound

Neosaxitoxin (NSTX) is included, as other saxitoxin-analogs, in a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). The parent compound of PSTs, saxitoxin (STX), is a tricyclic perhydropurine alkaloid, which can be substituted at various positions, leading to more than 30 naturally occurring STX analogues. All of them are related imidazoline guanidinium derivatives.

Pao turgidus is a species of freshwater pufferfish native to the Mekong basin. It may also occur in the Chao Phraya basin in Thailand. This species grows to a length of 18.5 centimetres (7.3 in) SL.

<i>Saxidomus gigantea</i> Species of bivalve

Saxidomus gigantea is a large, edible saltwater clam, a marine bivalve mollusk in the family Veneridae, the venus clams. It can be found along the western coast of North America, ranging from the Aleutian Islands to San Francisco Bay. Common names for this clam include butter clam, Washington clam, smooth Washington clam and money shell.

Alexandrium catenella is a species of dinoflagellates. It is among the group of Alexandrium species that produce toxins that cause paralytic shellfish poisoning, and is a cause of red tide. ‘’Alexandrium catenella’’ is observed in cold, coastal waters, generally at temperate latitudes. These organisms have been found in the west coast of North America, Japan, Australia, and parts of South Africa.

Dinotoxins are a group of toxins which are produced by flagellate, aquatic, unicellular protists called dinoflagellates. Dinotoxin was coined by Hardy and Wallace in 2012 as a general term for the variety of toxins produced by dinoflagellates. Dinoflagellates are an enormous group of marine life, with much diversity. With great diversity comes many different toxins, however, there are a few toxins that multiple species have in common.

<span class="mw-page-title-main">Gonyautoxin</span> Chemical compound

Gonyautoxins (GTX) are a few similar toxic molecules that are naturally produced by algae. They are part of the group of saxitoxins, a large group of neurotoxins along with a molecule that is also referred to as saxitoxin (STX), neosaxitoxin (NSTX) and decarbamoylsaxitoxin (dcSTX). Currently eight molecules are assigned to the group of gonyautoxins, known as gonyautoxin 1 (GTX-1) to gonyautoxin 8 (GTX-8). Ingestion of gonyautoxins through consumption of mollusks contaminated by toxic algae can cause a human illness called paralytic shellfish poisoning (PSP).

<span class="mw-page-title-main">Decarbamoylsaxitoxin</span> Chemical compound

Decarbamoylsaxitoxin, abbreviated as dcSTX, is a neurotoxin which is naturally produced in dinoflagellate. DcSTX is one of the many analogues of saxitoxin (STX).

<span class="mw-page-title-main">Zetekitoxin AB</span> Chemical compound

Zetekitoxin AB (ZTX) is a guanidine alkaloid found in the Panamanian golden frog Atelopus zeteki. It is an extremely potent neurotoxin.

References

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  2. ↑ Landsberg JH (2002). "The Effects of Harmful Algal Blooms on Aquatic Organisms". Reviews in Fisheries Science. 10 (2): 113–390. Bibcode:2002RvFS...10..113L. doi:10.1080/20026491051695. S2CID   86185142.
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  16. ↑ Fleming J. J., McReynolds M. D., Du Bois J. (2007). "(+)-Saxitoxin: a first and second generation stereoselective synthesis". Journal of the American Chemical Society. 129 (32): 9964–75. doi:10.1021/ja071501o. PMID   17658800.
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  20. 1 2 Kellmann R, Mihali TK, Jeon YJ, Pickford R, Pomati F, Neilan BA (2008). "Biosynthetic Intermediate Analysis and Functional Homology Reveal a Saxitoxin Gene Cluster in Cyanobacteria". Applied and Environmental Microbiology. 74 (13): 4044–4053. Bibcode:2008ApEnM..74.4044K. doi:10.1128/AEM.00353-08. PMC   2446512 . PMID   18487408.
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  23. ↑ Chang FC, Spriggs DL, Benton BJ, Keller SA, Capacio BR (1997). "4-Aminopyridine reverses saxitoxin (STX)- and tetrodotoxin (TTX)-induced cardiorespiratory depression in chronically instrumented guinea pigs". Fundamental and Applied Toxicology. 38 (1): 75–88. doi:10.1006/faat.1997.2328. PMID   9268607. S2CID   17185707.
  24. ↑ Chen H, Lin C, Wang T (1996). "Effects of 4-Aminopyridine on Saxitoxin Intoxication". Toxicology and Applied Pharmacology. 141 (1): 44–48. doi:10.1006/taap.1996.0258. PMID   8917674.
  25. ↑ "Paralytic shellfish poisoning (PSP)" (PDF). Fish Dept. Sabah Malaysia. Archived from the original (PDF) on October 25, 2021. Retrieved April 10, 2022.
  26. ↑ Stewart CE (2006). Weapons of Mass Casualties and Terrorism Response Handbook. Jones & Bartlett Learning. p. 175. ISBN   978-0-7637-2425-2 . Retrieved 4 May 2015.
  27. 1 2 3 Unauthorized Storage of Toxic Agents. Church Committee Reports. Vol. 1. The Assassination Archives and Research Center (AARC). 1975–1976. p. 7.
  28. 1 2 Wheelis M, Rozsa L, Dando M (2006). Deadly Cultures: Biological Weapons since 1945. President and Fellows of Harvard College. p. 39. ISBN   978-0-674-01699-6 . Retrieved 4 May 2015.
  29. ↑ Mauroni AJ (2000). America's Struggle with Chemical-biological Warfare. 88 Post Road West, Westport, CT 06881: Praeger Publishers. p. 50. ISBN   978-0-275-96756-7 . Retrieved 4 May 2015.{{cite book}}: CS1 maint: location (link)
  30. ↑ "Saxitoxin fact sheet" (PDF). Organisation for the Prohibition of Chemical Weapons (OPCW). June 2014.
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