Decarbamoylsaxitoxin

Last updated
Decarbamoylsaxitoxin
Decarbamoylsaxitoxin.svg
Structure of dcSTX
DcSTX ball and stick.png
Ball and stick model of dcSTX
DcSTX space filling molecule.png
Space filling molecule of dcSTX
Names
IUPAC name
(3aS,4R,10aS)-2,6-diamino-4-(hydroxymethyl)-3a,4,8,9-tetrahydro-3H-pyrrolo[1,2-c]purine-10,10-diol
Identifiers
3D model (JSmol)
ChemSpider
KEGG
PubChem CID
UNII
  • InChI=1S/C9H16N6O3/c10-6-13-5-4(3-16)12-7(11)15-2-1-8(17,18)9(5,15)14-6/h4-5,16-18H,1-3H2,(H2,11,12)(H3,10,13,14)/t4-,5-,9-/m0/s1
    Key: VRRIYZJUSNMZMP-PJPYAQQDSA-N
  • NC1=N[C@H]2[C@H](CO)N=C(N)N3CCC(O)(O)[C@]23N1
Properties
C9H16N6O3
Molar mass 256.26 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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

Contents

Figure 1: the structure of saxitoxin, with numbered carbons. Decarbamoylsaxitoxin is one of the derivatives of saxitoxin, which only has a CH2OH group on carbon 1. Also, a double bond between carbon 2 and 3 is added. STX numbered.png
Figure 1: the structure of saxitoxin, with numbered carbons. Decarbamoylsaxitoxin is one of the derivatives of saxitoxin, which only has a CH2OH group on carbon 1. Also, a double bond between carbon 2 and 3 is added.

Saxitoxin is a tricyclic alkaloid compound, which has multiple structural related neurotoxins. One of those related neurotoxins is neosaxitoxin (NSTX) in which the nitrogen at position 2 is not bound to a hydrogen, but to a hydroxyl group. Another toxic analogue of saxitoxin is gonyautoxin (GTX). The difference between GTX and STX is that on the carbon at position 11, a hydrogensulfate is bound.

Between dcSTX, NSTX and GTX, dcSTX is the one which varies most from saxitoxin. In dcSTX there is a double bond between carbons 2 and 3, while there is a single bond in STX. This also results in that the double-bonded N to carbon number 3 in STX, is a single bound NH2 in dcSTX. Another difference between decarbamoylsaxitoxin and saxitoxin is that the amino-carbonyl-oxy-methyl group at position 1 in STX, is only a CH2OH group in dcSTX.

Even though there are slight differences between all saxitoxin-related compounds, all those saxitoxins are neurotoxins which affect the sodium channels. When in contact with one of the saxitoxins it can cause a severe illness, which is known as paralytic shellfish poisoning (PSP).

Source in nature

From eating shellfish, under which mussels, clams, whelks and scallops, multiple illnesses can result. One of them is sensory and motor paralysis, known as paralytic shellfish poisoning (PSP), which results from ingestion of saxitoxin and its derivatives, such as decarbamoylsaxitoxin. [1] Shellfish can concentrate a dinoflagellate known as Gonyaulax tamarensis , which elaborates saxitoxin. [1] Mussels are known to filter up to 20 litres of water a day, which is why they are very likely to carry the toxin when the surrounding water is contaminated. [2] This dinoflagellate does not affect the shellfish, but when an organism eats the scallop shuckings, it risks getting poisoned. [1] Some species, such as the littleneck clam, possess an enzyme that converts saxitoxin into decarbamoylsaxitoxin, [3] which reportedly decreases the toxicity to humans of the saxitoxins present. [4]

Structure and synthesis

Structure and properties

Synonyms of decarbamoylsaxitoxin are; dcSTX-saxitoxin, decarbamoylsaxitoxin, decarbamylsaxitoxin

Synthesis

Decarbamoylsaxitocin is like saxitoxin a very hygroscopic solid. Since saxitoxins and their derivatives are mainly produced by the Gonyaulax tamarensis dinoflagellate, for a long time the exact synthesis pathway was unknown. Saxitoxin was the first paralytic shellfish toxin for which a total synthesis was described. This was done by Kishi and his research group in 1977. [5] [6] In 1991 they managed to describe the synthesis of decarbamoylsaxitoxin as well. [7]

Metabolism

Decarbamoylsaxitoxin enters the body via the mouth. There it can be absorbed through the mucosa, and later on it can be absorbed through the small intestine. [8] After absorption, the toxin is distributed through the body water. [8] It gets removed by the kidneys and is excreted via urine. [9]

An exact biotransformation of decarbamoylsaxitoxin is not known yet. In 2004, a study [10] on people who died from paralytic shellfish poisoning reported detected oxidation of saxitoxin into neosaxitoxin.

In a more recent study [9] on human liver samples, a metabolic pathway was proposed for saxitoxin which is shown in figure 2.[ needs update ] They found that saxitoxin can be converted into neosaxitoxin in the human body, which harmonizes the earlier research. The neosaxitoxin will however be converted further into either a sugar-binding state or into GTX4/GTX1, a pair of gonyautotoxin epimers. [9] These epimers can be converted to a sugar-binding state as well. Also, the sugar-bound state of saxitoxin can be formed. As this study shows, the phase II conjugation reaction is a very common glucoronidation reaction. Due to this, the substance gets more hydrophilic which makes it more easily excretable.

Even though this study was done on saxitoxin exclusively, it is very likely that the metabolic pathway of decarbamoylsaxitoxin will be the same, since the major structural difference between them is the shown OONH2 substituent, indicated with a yellow circle in the figure[ needs update ], which is a hydroxyl substituent in decarbamoylsaxitoxin. This group is not affected in the proposed metabolism and will most likely not interrupt the shown mechanism.

Mechanisms of action

Decarbamoylsaxitoxin is a known neurotoxin, which mechanism is based on that of saxitoxin. Both namely bind to sodium channels, as shown in figure 3 [11] [ needs update ] Sodium channels contain negative residues at the top of their pore. [12] These negatively charged residues are part of the filter for sodium. Decarbamoylsaxitoxin contains two guanidine substructures which can be protonated easily. Protonation of the guanidine substructures leads to a positive charge on the decarbamoylsaxitoxin and because of this positive charge the decarbamoylsaxitoxin can bind to the sodium channels. This binding to sodium channels prevents sodium passing through the channel. Because sodium passage is blocked, the channel cannot fulfil its function and it will be impossible to generate an action potential in the cell with the blocked sodium channels. There has been a study performed on which sodium channels are mainly targeted by the neurotoxin. [8] This study showed that the neuromuscular transmission in the motor axon and the muscular membrane is targeted whereas the end-plate is left unaffected. It also showed that the atrioventicular node is the main target inside the heart. The consequences of decarbamoylsaxitoxin are paralysis and death. In vitro tests declared decarbamoylsaxitoxin more toxic than saxitoxin. [13] It is not clear why this is the case; it can be speculated that it is caused by the alcohol group that is present on decarbamoylsaxitoxin instead of the amide group on saxitoxin. However, what can be concluded for sure is that decarbamoylsaxitoxin is converted into other compounds in the body or has trouble reaching the sodium channels. In vivo tests declared decarbamoylsaxitoxin half as toxic as saxitoxin. [14]

Illness and poisoning

Toxicology

In coastal waters, mostly in temperate and subtropical regions, dinoflagellate blooms can occur when the conditions for growth and aggregation are optimal. [2] They cause so called ‘red tides’ or ‘red waters’ and the concentration of toxic can be of great risk for both marine life and humans. [2] However, also when the water is clear shellfish can contain toxins, which are not destroyed by heating or freezing. [15] In case of a red tide, a mussel can contain as much as 180 g of toxin. [2] To human, a dose of only 1 mg saxitoxin can be fatal. [9] Worldwide the limits for toxins in shellfish which cause paralytic shellfish poisoning is set at 80 μg per 100 g of meat. [10]

Illness in humans

Usually, within minutes of ingestion of the poisoned shellfish, paranesthesia of the oral region and fingertips are noticed. [1] [16] This gradually proceeds to the neck, arms, legs and toes, together with general muscular incoordination. [1] Patients can start feeling numb, due to which it is hard to make voluntary movements. [16] Also symptoms as dizziness, weakness and incoherence can occur. In the final stage of the poisoning, respiratory distress and full muscular paralysis occur, usually between 2 and 12 hours after ingestion. [1]

The symptoms are sometimes difficult to interpret, since they are also associated with drunkenness. [2] Alcohol can increase the severity of symptoms. [1]

Treatment

There is no antidote to paralytic shellfish poisoning. However, with proper medical care, most patients will survive. The most important in treatment is assistance of the patient with ventilation. [1] Also alkaline and sodium-containing fluids can be used to block the effect of paralytic shellfish toxins on nerve conduction. [1]

DEREK prediction

Figure 4: The structure of decarbamoylsaxitoxin as inserted in Derek Nexus. Highlighted is the reactive group to which the Derek alert responds. This group is specified in the figure next to the structure. STX DEREK.png
Figure 4: The structure of decarbamoylsaxitoxin as inserted in Derek Nexus. Highlighted is the reactive group to which the Derek alert responds. This group is specified in the figure next to the structure.

A way to predict toxicity from structure, is with the help of a software programme like Derek Nexus v3.0.1. [17] It comes up with alerts that match your structure. In the case of decarbamoylsaxitoxin, for mammals the alert “Rapid prototype060: Methylene glycol or derivate” comes up, with a sureness “equivocal”, see figure 4.

This rapid prototype alert describes the nephrotoxicity of methylene glycol and its derivatives.

For this alert 731 chemicals were classified on basis of the causation of histopathologic lesions in the kidney in oral rat repeat dose studies, mostly with a duration of 28 days. It turns out that four compounds were really nephrotoxic. Because decarbamoylsaxitoxin is a geminal diol, it may be toxic for the kidneys.

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 and found in several other animals, it is actually produced by certain infecting or symbiotic bacteria like Pseudoalteromonas, Pseudomonas, and Vibrio as well as other species found in animals.

<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 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">Saxitoxin</span> Paralytic shellfish toxin

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).

<span class="mw-page-title-main">Tomalley</span> Lobster or crab organs eaten as a delicacy

Tomalley, crab fat, or lobster paste is the soft, green substance found in the body cavity of lobsters, that fulfills the functions of both the liver and the pancreas. Tomalley corresponds to the hepatopancreas in other arthropods. It is considered a delicacy, and may be eaten alone but is often added to sauces for flavour and as a thickening agent. The term lobster paste or lobster pâté can also be used to indicate a mixture of tomalley and lobster roe. Lobster bisque, lobster stock, and lobster consommé are made using lobster bodies (heads), often including tomalley.

<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.

Amnesic shellfish poisoning (ASP) is an illness caused by consumption of shellfish that contain the marine biotoxin called domoic acid. In mammals, including humans, domoic acid acts as a neurotoxin, causing permanent short-term memory loss, brain damage, and death in severe cases.

<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">Neurotoxic shellfish poisoning</span> Syndrome of shellfish poisoning

Neurotoxic shellfish poisoning (NSP) is caused by the consumption of brevetoxins, which are marine toxins produced by the dinoflagellate Karenia brevis. These toxins can produce a series of gastrointestinal and neurological effects. Outbreaks of NSP commonly take place following harmful algal bloom (HAB) events, commonly referred to as "Florida red tide". Algal blooms are a naturally-occurring phenomenon, however their frequency has been increasing in recent decades at least in-part due to human activities, climate changes, and the eutrophication of marine waters. HABs have been occurring for all of documented history, evidenced by the Native Americans' understanding of the dangers of shellfish consumption during periods of marine bioluminescence. Blooms have been noted to occur as far north as North Carolina and are commonly seen alongside the widespread death of fish and sea birds. In addition to the effects on human health, the economic impact of HAB-associated shellfish toxin outbreaks can have significant economic implications as well due to not only the associated healthcare costs, but the adverse impact on the commercial shellfish industry.

<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>Gonyaulax</i> Genus of single-celled organisms

Gonyaulax is a genus of dinoflagellates with the type species Gonyaulax spinifera Diesing. Gonyaulax belongs to red dinoflagellates and commonly causes red tides. It secretes a poisonous toxin known as "saxitoxin" which causes paralysis in humans.

<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.

Alexandrium is a genus of dinoflagellates. It contains some of the dinoflagellate species most harmful to humans, because it produces toxic harmful algal blooms (HAB) that cause paralytic shellfish poisoning (PSP) in humans. There are about 30 species of Alexandrium that form a clade, defined primarily on morphological characters in their thecal plates.

<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.

Canadian Reference Materials (CRM) are certified reference materials of high-quality and reliability produced by the National Metrology Institute of Canada – the National Research Council Canada. The NRC Certified Reference Materials program is operated by the Measurement Science and Standards portfolio and provides CRMs for environmental, biotoxin, food, nutritional supplement, and stable isotope analysis. The program was established in 1976 to produce CRMs for inorganic and organic marine environmental analysis and remains internationally recognized producer of CRMs.

<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).

References

  1. 1 2 3 4 5 6 7 8 9 Acres, J (1978). "Paralytic Shellfish Poisoning". CMAJ. 119 (10): 1195–1197. PMC   1818532 . PMID   570450.
  2. 1 2 3 4 5 Alaska Division of Public Health: Prevention Promotion Protection. "Paralytic Shellfish Poisoning Fact Sheet." Accessed on March 12, 2017
  3. ↑ Sullivan, John J.; Iwaoka, Wayne T.; Liston, John (1983). "Enzymatic transformation of PSP toxins in the littleneck clam (Protothaca staminea)". Biochemical and Biophysical Research Communications . 114 (2): 465–472. doi:10.1016/0006-291X(83)90803-3. PMID   6882435.
  4. ↑ Deeds, Jonathan R.; Landsberg, Jan H.; Etheridge, Stacey M.; Pitcher, Grant C.; Longan, Sara Watt (2008). "Non-Traditional Vectors for Paralytic Shellfish Poisoning". Marine Drugs . 6 (2): 308–348. doi: 10.3390/md6020308 . PMC   2525492 . PMID   18728730.
  5. ↑ Iwamoto, O; Akimoto, T; Nagasawa, K (2012). "Synthesis of saxitoxins". Pure and Applied Chemistry. 84 (6): 1445–1453. doi: 10.1351/pac-con-11-09-10 . S2CID   98176615.
  6. ↑ Tanino, H; Nakata, T; Kaneko, T (1977). "A stereospecific total synthesis of dl-saxitoxin". Journal of the American Chemical Society. 99 (8): 2818–2819. doi:10.1021/ja00450a079. PMID   850038.
  7. ↑ Yong Hong, C; Kishi, Y (1992). "Enantioselective total synthesis of (-)-Decarbamoylsaxitoxin". Journal of the American Chemical Society. 114 (18): 7001–7006. doi:10.1021/ja00044a008.
  8. 1 2 3 Halstead, B.W.; Schantz, E.J. (1984). "Paralytic Shellfish Poisoning". Switzerland: World Health Organization Geneva (79): 1–59. PMID   6610258.
  9. 1 2 3 4 Garcia, C.; Barriga, A.; Diaz, J.C. (2010). "Route of metabolization and detoxification of paralytic shellfish toxins in humans". Toxicon. 55 (1): 135–144. doi:10.1016/j.toxicon.2009.07.018. hdl: 10533/141436 . PMID   19632259.
  10. 1 2 Garcia, C.; Bravo, M.C.; Lagos, M. (2004). "Paralytic shellfish poisonging: post-mortem analysis of tissue and body fluid samples from human victims in the Patagonia fjords". Toxicon. 43 (2): 149–158. doi:10.1016/j.toxicon.2003.11.018. hdl: 10533/175125 . PMID   15019474.
  11. ↑ "Saxitoxin". Equatox. 2010. Retrieved March 15, 2017.
  12. ↑ Marban, E.; Yamagishi, T.; Tomaselli, G.F. (1998). "Structure and function of voltage-gated sodium channels". The Journal of Physiology. 508 (3): 647–657. doi:10.1111/j.1469-7793.1998.647bp.x. PMC   2230911 . PMID   9518722.
  13. ↑ Perez, S.; Vale, C.; Botana, A.M. (2011). "Determination of toxicity equivalent factors for paralytic shellfish toxins by electrophysiological measurements in cultured neurons". Chemical Research in Toxicology. 24 (7): 1153–1157. doi:10.1021/tx200173d. PMID   21619049.
  14. ↑ Suzuki, H.; Machii, K. (2014). "Comparison of Toxicity between Saxitoxin and Decarbamoylsaxitoxin in the Mouse Bioassay for Paralytic Shellfish Poisoning Toxins". Journal of Veterinary Medical Science. 76 (11): 1523–1525. doi: 10.1292/jvms.14-0211 . PMC   4272987 . PMID   25213205.
  15. ↑ Shin, C.; Jang, H.; Jo, H. (2017). "Development and validation of an accurate and sensitive LC-ESI-MS/MS method for the simultaneous determination of paralytic shellfish poisoning toxins in shellfish and tunicate". Food Control. 77: 171–178. doi:10.1016/j.foodcont.2017.02.034.
  16. 1 2 Popkiss, M.E.E; Horstman, D.A.; Harpur, D. (1979). "Paralytic Shellfish Poisoning". SA Medical Journal. 55 (25): 1017–1023.
  17. ↑ Derek Nexus (version v.3.0.1) [software that gives toxicity predictions]. Leeds: Lhasa Unlimited
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