Detail:

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

        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 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 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.

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. Oxidation of saxitoxin generates a highly fluorescent purine derivative which has been utilized to detect its presence.

        Several total syntheses of saxitoxin have been accomplished.

          Although saxitoxin biosynthesis 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.

          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.

        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.

        The proposed biosynthetic pathway of saxitoxin in cyanobacteria

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.

Toxicology:

        Saxitoxin 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 (1/8th of a medium-sized grain of sand) is lethal if ingested and the lethal dose by injection is about ten times lower (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.

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 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.

        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, 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.

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. It is known that saxitoxin was developed for both overt military use as well as for covert purposes by the CIA. Among weapons stockpiles were M1 munitions that contained either saxitoxin or botulinum toxin or a mixture of both. 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 Nixon, the US stockpiles of saxitoxin were destroyed, and development of saxitoxin as a military weapon ceased. 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.

        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.

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