Saxitoxin: Wikis

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Saxitoxin
Identifiers
CAS number 35523-89-8 Yes check.svgY
PubChem 37165
SMILES
Properties
Molecular formula C10H17N7O4
Molar mass 299.29 g mol−1
 Yes check.svgY (what is this?)  (verify)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Saxitoxin (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] Ingestion of saxitoxin (usually through shellfish contaminated by toxic algal blooms) is responsible for the human illness known as paralytic shellfish poisoning (PSP). In fact, the term saxitoxin originates from the species name of the butter clam (Saxidomus giganteus) in which it was first recognized. Saxitoxin, one of the most potent natural toxins known, acts on the voltage-gated sodium channels of nerve cells, preventing normal cellular function and leading to paralysis. The term saxitoxin can also refer to the entire suite of related neurotoxins produced by these microorganisms, which include pure saxitoxin (STX), neosaxitoxin (neoSTX), the gonyautoxins (GTX) and decarbamoylsaxitoxin (dcSTX). Detection of saxitoxin 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.

STX has been found in at least 12 marine and freshwater puffer fish species in Asia. However, the ultimate source of STX is 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.[3],[4] 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.[5] The various concentrations in puffer fish from the United States are similar to those found in the Philippines, Thailand,[4] Japan,[6] and South American countries.[7]

Contents

Mechanism

Saxitoxin is a neurotoxin that acts as a selective sodium channel blocker. [8]

Biosynthesis

Biosynthesis

Although STX biosynthesis seems complex, organisms from the two kingdoms, species of marine dinoflagellates and freshwater cyanobacteria, are capable of making these toxins by the same biosynthetic pathway.[9] The enzymes involved in the biosynthesis of STX have not been identified by previous studies.[10],[11],[12]

Saxitoxin synthesis is the first non-terpene alkaloid pathway described for bacteria. A complete STX biosynthetic gene cluster (sxt) is used to obtain a more favourable reaction. The predicted reaction sequence of suggested SxtA, based on its primary structure, is the loading of the ACP with acetate from acetyl-CoA, followed by SxtA-catalyzed methylation of acetyl-ACP, which is then converted to propionyl-ACP. Later another SxtA performs a Claisen condensation reaction between propionyl-ACP and arginine producing 4.

SxtG transfers an amidino group from arginine to the α-amino 4 group producing 5, which later undergoes retroaldol-like condensation by SxtB. SxtD adds a double bond between C-1 and C-5 of 6, which gives rise to the 1,2-H shift between C-5 and C-6 in 7. SxtS performs an epoxidation of the double bond and opening of the epoxide to an aldehyde. SxtU reduces the terminal aldehyde group of the STX precursor 9 forming 10. SxtI catalyzes the transfer of a carbamoyl group to the free hydroxyl group on 10. SxtH and SxtT perform a similar function which is the consecutive hydroxylation of C-12 terminating the STX biosynthetic pathway. This is only a proposed biosynthetic pathway, the actual mechanism of how substrates bind to the enzymes is still unknown.

Synthesis

The challenge for chemical synthesis comes from the dense arrangement of heteroatoms on the tricyclic structure and the dicationic nature of STX further complicates the purification of the target molecule.

The starting material of this synthesis is a commercially available compound, a glycerol-derived sulfamate ester 12. This is oxidized to form a product N,O-acetal 13 and is alkynylated with zinc reagent and BF3•OEt2, producing 14 and a subsequent reaction of tosylation at the C10 of the substituted [1,2,3]-oxathiazinane-2,2-dioxide heterocycle, which later undergoes azide displacement of the primary tosylate 15. The p-methoxybenzyl (PMB) is used to protect the NH group by alkylation 16 before performing a reduction of azide with Me3P and a p-methoxybenzenesulfonyl (Mbs) containing compound to produce isothiourea 17. With the PMB and Mbs protecting groups, another azide is introduced at C6, losing PMB under oxidative condition 19. An imidoyl chloride, MbsN=CCl2, is used to re-protect the nitrogen near the tosylate site, before activating the oxathiazinane heterocycle by hydrolysis. At this point, 20, all the required carbon in tricyclic structure of STX is obtained. Next, Me3P is used to reduce azide which is then treated with AgNO3 resulting in carbodiimide formation and ring closure 23. Adding trichloroacetyl isocyanate, 23 is converted to carbamate derivative of STX 24 which can be easily isolated. The 4 double bonds on 24 are then oxidized which shows the efficiency of this synthetic route. An addition of another bicycle reagent of B(O2CCF3) in acid produces beta-STXol, while stabilizing the carbamate side chain. The last step of the synthesis is to oxidize on the carbon with hydroxyl group with DCC, DMSO, C5H5N•HO2CCF3. The product can be highly purified using CH3CN, H2O and 10 mM heptafluorobutyric acid, giving overall yield of 1.3%. [13]

Human illness

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.

Military Interest

It is listed in schedule 1 of the Chemical Weapons Convention. According to the book Spycraft, U-2 spyplane pilots were provided with needles containing saxitoxin to be used for suicide in the event escape was impossible.[citation needed] The United States military isolated saxitoxin and assigned it the chemical weapon designation TZ.

For a lung effect by aerosol, the median lethal dosage (LCt50) of TZ is 5 mg·min/. Due to its high aerobiological decay rate (e.g., ~17%/min) and production cost, it was weaponized in tainted flechettes for special operations.

Though its early isolation and characterization were from military efforts, saxitoxin has been more important to cellular research in delineating the function of the sodium channel.

See also

References

  1. ^ a b Clark RF, Williams SR, Nordt SP, Manoguerra AS (1999). "A review of selected seafood poisonings". Undersea Hyperb Med 26 (3): 175–84. PMID 10485519. http://archive.rubicon-foundation.org/2314. Retrieved 2008-08-12. 
  2. ^ Landsberg JH, 2002. The effects of harmful algal blooms on aquatic organisms. Reviews in Fisheries Science, 10(2): 113–390.
  3. ^ Smith, E. A.; Grant, F.; Ferguson, C. M.; Gallacher, S. Biotransformations of paralytic shellfish toxins by bacteria isolated from bivalve molluscs. Appl. Environ. Microbiol. 2001, 67, 2345-2353.
  4. ^ a b Sato, S.; Kodama, M.; Ogata, T.; Saitanu, K.; Furuya, M.; Hirayama, K.; Kakinuma, K. Saxitoxin as a toxic principle of a freshwater puffer, Tetraodon fangi, in Thailand. Toxicon 1997, 35, 137-140.
  5. ^ 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, E. L.; Etheridge, S. M.; Deeds, J. R.; Van Dolah, F. M.; Leighfield, T. A.; Zou, Y.; Beaudry, C. G.; Benner, R. A.; Rogers, P. L.; Scott, P. S.; Kawabata, K.; Wolny, J. L.; Steidinger, K. A. Saxitoxin puffer fish poisoning in the United States, with the first report of Pyrodinium bahamense as the putative toxin source. Environ. Health Perspect. 2006, 114, 1502-1507.
  6. ^ Deeds, J. R.; Landsberg, J. H.; Etheridge, S. M.; Pitcher, G. C.; Longan, S. W. Non-traditional vectors for paralytic shellfish poisoning. Mar. Drugs 2008, 6, 308-348.
  7. ^ Lagos, N.; Onodera, H.; Zagatto, P. A.; Andrinolo, D.; Azevedo, S. M.; Oshima, Y. The first evidence of paralytic shellfish toxins in the fresh water cyanobacterium Cylindrospermopsis raciborskii, isolated from Brazil. Toxicon 1999, 37, 1359-1373.
  8. ^ Huot RI, Armstrong DL, Chanh TC (June 1989). "Protection against nerve toxicity by monoclonal antibodies to the sodium channel blocker tetrodotoxin". J. Clin. Invest. 83 (6): 1821–6. doi:10.1172/JCI114087. PMID 2542373. 
  9. ^ Shimizu, Y. Microalgal metabolites. Curr. Opin. Microbiol. 2003, 6, 236-243.
  10. ^ Pomati, F.; Burns, B. P.; Neilan, B. A. Identification of an Na(+)-dependent transporter associated with saxitoxin-producing strains of the cyanobacterium Anabaena circinalis. Appl. Environ. Microbiol. 2004, 70, 4711-4719.
  11. ^ Shimizu, Y.; Norte, M.; Hori, A.; Genenah, A.; Kobayashi, M. Biosynthesis of saxitoxin analogs: the unexpected pathway. J. Am. Chem. Soc. 1984, 106, 6433-6434.
  12. ^ Kellmann, R.; Mihali, T. K.; Jeon, Y. J.; Pickford, R.; Pomati, F.; Neilan, B. A. Biosynthetic intermediate analysis and functional homology reveal a saxitoxin gene cluster in cyanobacteria. Appl. Environ. Microbiol. 2008, 74, 4044-4053.
  13. ^ Fleming, J. J.; McReynolds, M. D.; Du Bois, J. (+)-saxitoxin: a first and second generation stereoselective synthesis. J. Am. Chem. Soc. 2007, 129, 9964-9975

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