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

The term saxitoxin originates from the genus name of the butter clam ( ) 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 , and which includes saxitoxin itself (STX), (NSTX), (GTX) and decarbamoylsaxitoxin (dcSTX).

Saxitoxin has a large environmental and economic impact, as its presence in shellfish such as , , and frequently leads to bans on commercial and recreational shellfish harvesting in many temperate coastal waters around the world including the Northeastern and Western , , , , , and . In the United States, paralytic shellfish poisoning has occurred in , , Washington, , and .


Source in nature
Saxitoxin is a naturally produced by certain species of marine ( Alexandrium sp., sp., sp.) and freshwater cyanobacteria ( Dolichospermum cicinale sp., some spp., Cylindrospermopsis sp., sp., sp.) Saxitoxin accumulates in "planktivorous , including (bivalves and ), , and ".

Saxitoxin has also been found in at least twelve marine species in Asia and one freshwater fish in . The ultimate source of STX is often still uncertain. The dinoflagellate Pyrodinium bahamense is the source of STX found in . 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 . Even after a year of captivity, Landsberg et al. found the skin mucus remained highly toxic. The concentrations in puffer fish from the United States are similar to those found in the Philippines, Thailand, Japan, and South American countries. Puffer fish also accumulate a structurally distinct toxin, .For a more comprehensive discussion of TTX-producing bacterial species associated with metazoans from which the toxin has been isolated or toxicity observed, and biosynthesis, see


Structure and synthesis
Saxitoxin is an solid, but X-ray crystallography of crystalline derivatives enabled the structure of saxitoxin to be determined. of saxitoxin generates a highly derivative which has been utilized to detect its presence.

Several of saxitoxin have been accomplished.


Mechanism of action
Saxitoxin is a neurotoxin that acts as a selective, reversible, voltage-gated sodium channel blocker.
(2015). 9780128004944, Academic Press.
One of the most potent known natural toxins, it acts on the voltage-gated sodium channels of , preventing normal cellular function and leading to .

The voltage-gated sodium channel is essential for normal neuronal functioning. It exists as integral membrane proteins interspersed along the of a neuron and possessing four that span the . Opening of the voltage-gated sodium channel occurs when there is a change in or some 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 . 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 . 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 described above.


Biosynthesis
Although the of saxitoxin seems complex, organisms from two different kingdoms, indeed two different domains, species of marine 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 required for saxitoxin synthesis.

Saxitoxin biosynthesis is the first non-terpene 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 is still unknown, and genes involved in the biosynthesis of saxitoxin are either putative or have only recently been identified.

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 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 , 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 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 of the double bond yielding intermediate 8, and then an opening of the epoxide to an , 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 , fatal at only 5 μg/kg when injected intramuscularly. The median lethal dose (LD50) for mice is very similar with varying administration routes: i.v. is 3.4 μg/kg, i.p. is 10 μg/kg and is 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 one-tenth of that (approximately 0.6 μg/kg). The human inhalation toxicity of 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.


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".

The medical and environmental importance of saxitoxin derives from the consumption of contaminated and certain finfish which can concentrate the toxin from dinoflagellates or cyanobacteria. The blocking of neuronal which occurs in PSP produces a flaccid paralysis that leaves its victim calm and conscious through the progression of . Death often occurs from respiratory failure. PSP toxins have been implicated in various marine animal mortalities involving of the toxin from its algal source up the food chain to higher .

Studies in animals have shown that the lethal effects of saxitoxin can be reversed with 4-aminopyridine, 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 is administered or the poison wears off.


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 by the US military.
(2025). 9780763724252, Jones & Bartlett Learning. .
It is known that saxitoxin was developed for both overt military use as well as for covert purposes by the . Among weapons stockpiles were M1 munitions that contained either saxitoxin, or a mixture of both.
(2025). 9780674016996, President and Fellows of Harvard College. .
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.

After the 1969 ban on biological warfare by President , the US stockpiles of saxitoxin were destroyed, and development of saxitoxin as a military weapon ceased.

(2025). 9780275967567, Praeger Publishers. .
In 1975, the CIA reported to Congress that it had kept a small amount of saxitoxin and venom against Nixon's orders which was then destroyed or distributed to researchers.

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

External links

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