Saxitoxin

Source: Wikipedia, the free encyclopedia.
Saxitoxin
Skeletal formula
Ball-and-stick model
Space-filling model
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 Edit this at Wikidata
IUPHAR/BPS
KEGG
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 ☒N
    Key: RPQXVSUAYFXFJA-HGRQIUPRSA-N ☒N
  • 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).
☒N verify (what is checkY☒N ?)

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).

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

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

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

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 di

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.
Main article: Sodium channel blocker

Saxitoxin is a neurotoxin that acts as a

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

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.

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.

Illness and poisoning

Toxicology

Saxitoxin is highly toxic to

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

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

See also: United States biological weapons program

Saxitoxin, by virtue of its extremely low

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

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

chemical weapon designation TZ.[30]

See also

References

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    PMID 10485519. Archived from the original on October 7, 2008. Retrieved 2008-08-12.{{cite journal}}: CS1 maint: unfit URL (link
    )
  2. S2CID 86185142
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  3. ^ a b c d e "Saxitoxin". Retrieved April 10, 2022.
  4. PMID 19560484
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  5. PMID 11319121
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  6. ^
    PMID 9028016
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  7. PMID 17035133
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  8. PMID 18728730
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  9. PMID 10414862
    .
  10. PMID 21543051. Archived from the original
    (PDF) on 2016-03-05. Retrieved 2022-04-10.
  11. PMID 1176726
    .
  12. PMID 1133383
    .
  13. PMID 621331
    .
  14. PMID 850038
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  15. PMID 22098556
    .
  16. PMID 17658800
    .
  17. OCLC 903965588.{{cite book}}: CS1 maint: others (link
    )
  18. PMID 2542373
    .
  19. ^
    PMID 21625593
    .
  20. ^
    PMID 18487408
    .
  21. ISSN 1057-9419
    . Retrieved 26 May 2012.
  22. ^ Benton BJ, Keller SA, Spriggs DL, Capacio BR, Chang FC (1998). "Recovery from the lethal effects of saxitoxin: A therapeutic window for 4-aminopyridine (4-AP)". Toxicon. 36 (4): 571–588.
    PMID 9643470
    .
  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.
    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.
    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. ISBN 978-0-7637-2425-2
    . Retrieved 4 May 2015.
  27. ^ a b c Unauthorized Storage of Toxic Agents. Church Committee Reports. Vol. 1. The Assassination Archives and Research Center (AARC). 1975–1976. p. 7.
  28. ^
    ISBN 978-0-674-01699-6
    . Retrieved 4 May 2015.
  29. 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.

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Saxitoxin&oldid=1198051471"