Chemistry:Azaspiracid

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Azaspiracid-1
Chemical structure of Azaspiracid
Identifiers
3D model (JSmol)
Abbreviations AZA
ChemSpider
UNII
Properties
C47H71NO12
Molar mass 842.07 g mol-1
Appearance Colorless
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references
Tracking categories (test):

Azaspiracids (AZA) are a group of polycyclic ether marine algal toxins produced by the small dinoflagellate Azadinium spinosum that can accumulate in shellfish and thereby cause illness in humans.[1][2]

Azaspiracid was first identified in the 1990s following an outbreak of human illness in the Netherlands that was associated with ingestion of contaminated shellfish originating from Killary Harbour, Ireland. To date, over 20 AZA analogues have been identified in phytoplankton and shellfish.[3][4][5][6][7][8][9][10] Over the last 15 years, AZAs have been reported in shellfish from many coastal regions of western Europe,[11][12][13][14][15] Northern Africa,[16][17] South America,[18][19] and North America. In addition, AZAs have been found in Japanese sponges[20] and Scandinavian crabs.[21] Not surprisingly, the global distribution of AZAs appears to correspond to the apparent wide spread occurrence of Azadinium.[22][23][24] Empirical evidence is now available that unambiguously demonstrates the accumulation of AZAs in shellfish via direct feeding on AZA-producing A. spinosum.[25][26]

Mechanism of action

Azaspiracid is a phycotoxin that inhibits hERG voltage-gated potassium channels.[27]

Human Illness

Unlike many other marine phycotoxins, little is known about the AZA toxin class. Similar to DSP toxins, human consumption of AZA-contaminated shellfish can result in severe acute symptoms that include nausea, vomiting, diarrhea, and stomach cramps.[13] Azaspiracid has an EU established regulatory limit of 160 μg/kg. Within the United States, the FDA has established an action level for AZP of 0.16ppm (160 μg/kg) azaspiracid equivalents which is consistent with that currently employed in the EU. To date, six human azaspiracid poisoning (AZP) events have been confirmed, but it is quite possible, due to the similarity of symptoms observed for people with DSP or other types of food poisoning (e.g., bacterial enteritis), that many more undocumented events have occurred. Coincidentally, each of the confirmed AZP events have been traced to contaminated Irish shellfish (Mytilus edulis).

Analogues of Azaspiracid

The first confirmed AZP event occurred in November 1995. Mussels harvested from Killary Harbour, Ireland were exported to The Netherlands, resulting in eight people falling ill with DSP-like symptoms of gastrointestinal illness, including nausea, vomiting, severe diarrhea, and stomach cramps.[3][28][29] The absence of known DSP toxins okadaic acid and dinophysistoxin-2 led to the discovery and identification of a novel etiological agent, temporarily called Killary Toxin-3 before being renamed to AZA1.[3] Mussels collected from the same area five months after the event were shown to contain (in μg/g whole meat) AZA1 (1.14), AZA2 (0.23), and AZA3 (0.06).[9]

In September/October 1997, as few as 10-12 AZA-contaminated mussels were consumed by individuals in the Arranmore Island region of Donegal, Ireland. At least 20-24 people were believed to have been exposed to AZAs in this event, but only eight sought medical attention. Symptoms included nausea, vomiting, and diarrhea for 2–5 days prior to full recovery. Analysis of the shellfish revealed five AZA analogues, AZA1-5, with most of the toxin concentrated in the digestive glands[8][9] at levels exceeding 30 μg/g (estimated at 6 μg/g whole mussel meat). The AZAs persisted in the mussels at elevated levels for at least eight months.[citation needed]

In September 1998, mussels exported from Clew Bay, Ireland to Ravenna, Italy were consumed and ten people fell victim to AZP with typical gastrointestinal symptoms. Digestive glands were shown to contain ~1 μg/g AZAtotal with three AZA analogues present (in μg/g digestive gland): AZA1 (0.5), AZA2 (0.06), and AZA3 (0.44).[citation needed]

Also in September 1998, a large shipment of mussels from Bantry Bay, Ireland was sent to France, resulting in an estimated 20-30 human illnesses due to AZP. Ironically, these shellfish has been tested ahead of time and deemed safe according to the DSP mouse bioassay; however, it was later determined that the DSP mouse bioassay is susceptible to false negatives for the AZA toxins. Coincidentally, the French government posed an embargo on the import of Irish shellfish for most of 1999. Follow-up analysis of the shellfish by LC/MS determined that high levels of AZA were present (up to 1.5 μg/g whole meat).[citation needed]

In August 2000, between 12-16 people from various regions (Warrington, Alyesbury, Isle of Wight, Sheffield) of the United Kingdom were intoxicated following the consumption of frozen, pre-cooked mussels that originated from Bantry Bay, Ireland. Symptoms included nausea, diarrhea, abdominal pain, and cramps. These mussels were also deemed safe for human consumption based on results from mouse bioassays; however, LC/MS analysis determined the presence of AZA1-3 in an uneaten portion from this same batch. Toxin concentrations were 0.85 μg/g shellfish meat (not including the digestive gland), which likely represented an underestimation of the total concentration.[28]

In 2008, an AZP event occurred in the United States in July. Frozen, pre-cooked mussels from Bantry Bay, Ireland were exported and intoxicated two people. It is estimated that each person ate between 113 and 340 grams of shellfish. Within five hours following the meal, each person experienced abdominal heaviness, vomiting (5-15 times), and diarrhea for up to 30 hours. Analysis of similar products with the same lot number revealed the presence of AZA1-3 with up to 0.244 μg AZAtotal/g tissue.[30] As a result of this event, over 150 tonnes of commercial product were removed from the market and voluntarily destroyed by the manufacturer.[citation needed]

Chemistry

The general structure of AZA1 (MW 841.5) was first reported in 1998 after successful isolation from Irish blue mussel (Mytilus edulis) material.[3] A cyclic amine (or aza group), a unique tri-spiro-assembly and a carboxylic acid group gave rise to the name AZA-SPIR-ACID. The original structure reported in 1998 was found to contain several errors, first indicted by an empirical demonstration of the contra-thermodynamic configurational assignment of the relative configuration at the C13 ketal center,[31] and followed by attempts carried out in 2003.[32][33] The purported synthesized AZA1 structure was found to have a different chromatographic behavior and discrepancies in its nuclear magnetic resonance (NMR) spectrum compared to the compound isolated from natural sources. Further extensive study including sophisticated synthetic chemistry resulted in structure revision in 2004.[34][35][36] In 2018, a comprehensive synthetic and analytical study was published that provided a structural revision that corrects all previous published azaspiracid structural assignments.[37] Specifically, the primary azaspiracids were assigned the (6R,10R,13R,14R,16R,17R,19S,20S,21R,24S,25S,28S,30S,32R,33R,34R,36S,37S,39R)-absolute configurations. Thus, the structures of azaspiracids presented on this Wikipedia page should also be revised to reflect the 20S absolute configuration.

References

  1. ↑ Tillmann, Urban; Elbrächter, Malte; Krock, Bernd; John, Uwe; Cembella, Allan (2009). "Azadinium spinosumgen. Et sp. Nov. (Dinophyceae) identified as a primary producer of azaspiracid toxins". European Journal of Phycology 44: 63–79. doi:10.1080/09670260802578534. 
  2. ↑ Krock, Bernd; Tillmann, Urban; John, Uwe; Cembella, Allan D. (2009). "Characterization of azaspiracids in plankton size-fractions and isolation of an azaspiracid-producing dinoflagellate from the North Sea". Harmful Algae 8 (2): 254–63. doi:10.1016/j.hal.2008.06.003. 
  3. ↑ 3.0 3.1 3.2 3.3 Satake, Masayuki; Ofuji, Katsuya; Naoki, Hideo; James, Kevin J.; Furey, Ambrose; McMahon, Terry; Silke, Joe; Yasumoto, Takeshi (1998). "Azaspiracid, a New Marine Toxin Having Unique Spiro Ring Assemblies, Isolated from Irish Mussels, Mytilus edulis". Journal of the American Chemical Society 120 (38): 9967–8. doi:10.1021/ja981413r. 
  4. ↑ James, Kevin J.; Sierra, Monica Diaz; Lehane, Mary; Braña Magdalena, Ana; Furey, Ambrose (2003). "Detection of five new hydroxyl analogues of azaspiracids in shellfish using multiple tandem mass spectrometry". Toxicon 41 (3): 277–83. doi:10.1016/S0041-0101(02)00288-X. PMID 12565749. 
  5. ↑ Jauffrais, Thierry; Kilcoyne, Jane; Séchet, Véronique; Herrenknecht, Christine; Truquet, Philippe; Hervé, Fabienne; Bérard, Jean Baptiste; Nulty, Cíara et al. (2012). "Production and Isolation of Azaspiracid-1 and -2 from Azadinium spinosum Culture in Pilot Scale Photobioreactors". Marine Drugs 10 (12): 1360–82. doi:10.3390/md10061360. PMID 22822378. 
  6. ↑ Furey, Ambrose; Braña-Magdalena, Ana; Lehane, Mary; Moroney, Cian; James, Kevin J.; Satake, Masayuki; Yasumoto, Takeshi (2002). "Determination of azaspiracids in shellfish using liquid chromatography/tandem electrospray mass spectrometry". Rapid Communications in Mass Spectrometry 16 (3): 238–42. doi:10.1002/rcm.560. PMID 11803546. Bibcode: 2002RCMS...16..238F. 
  7. ↑ McCarron, Pearse; Kilcoyne, Jane; Miles, Christopher O.; Hess, Philipp (2009). "Formation of Azaspiracids-3, -4, -6, and -9 via Decarboxylation of Carboxyazaspiracid Metabolites from Shellfish". Journal of Agricultural and Food Chemistry 57 (1): 160–9. doi:10.1021/jf8025138. PMID 19055365. https://nrc-publications.canada.ca/eng/view/fulltext/?id=234623c5-7987-4198-8b10-fb62cad8c4ac. 
  8. ↑ 8.0 8.1 Ofuji, Katsuya; Satake, Masayuki; McMahon, Terry; James, Kevin J.; Naoki, Hideo; Oshima, Yasukatsu; Yasumoto, Takeshi (2014). "Structures of Azaspiracid Analogs, Azaspiracid-4 and Azaspiracid-5, Causative Toxins of Azaspiracid Poisoning in Europe". Bioscience, Biotechnology, and Biochemistry 65 (3): 740–2. doi:10.1271/bbb.65.740. PMID 11330704. 
  9. ↑ 9.0 9.1 9.2 Ofuji, Katsuya; Satake, Masayuki; McMahon, Terry; Silke, Joe; James, Kevin J.; Naoki, Hideo; Oshima, Yasukatsu; Yasumoto, Takeshi (1999). "Two analogs of azaspiracid isolated from mussels, Mytilus edulis, involved in human intoxication in Ireland". Natural Toxins 7 (3): 99–102. doi:10.1002/(SICI)1522-7189(199905/06)7:3<99::AID-NT46>3.0.CO;2-L. PMID 10647511. 
  10. ↑ Rehmann, Nils; Hess, Philipp; Quilliam, Michael A. (2008). "Discovery of new analogs of the marine biotoxin azaspiracid in blue mussels (Mytilus edulis) by ultra-performance liquid chromatography/tandem mass spectrometry". Rapid Communications in Mass Spectrometry 22 (4): 549–58. doi:10.1002/rcm.3385. PMID 18228242. Bibcode: 2008RCMS...22..549R. 
  11. ↑ Magdalena, Ana Braña; Lehane, Mary; Krys, Sophie; Fernández, Mariá Luisa; Furey, Ambrose; James, Kevin J (2003). "The first identification of azaspiracids in shellfish from France and Spain". Toxicon 42 (1): 105–8. doi:10.1016/S0041-0101(03)00105-3. PMID 12893067. 
  12. ↑ James, Kevin J; Furey, Ambrose; Lehane, Mary; Ramstad, Hanne; Aune, Tore; Hovgaard, Peter; Morris, Steven; Higman, Wendy et al. (2002). "First evidence of an extensive northern European distribution of azaspiracid poisoning (AZP) toxins in shellfish". Toxicon 40 (7): 909–15. doi:10.1016/S0041-0101(02)00082-X. PMID 12076644. 
  13. ↑ 13.0 13.1 Twiner, Michael; Rehmann, N; Hess, P; Doucette, G. J. (2008). "Azaspiracid Shellfish Poisoning: A Review on the Chemistry, Ecology, and Toxicology with an Emphasis on Human Health Impacts". Marine Drugs 6 (2): 39–72. doi:10.3390/md20080004. PMID 18728760. 
  14. ↑ Furey, Ambrose; Moroney, Cian; Magdalena, Ana Braña; Fidalgo Saez, Maria José; Lehane, Mary; James, Kevin J. (2003). "Geographical, Temporal, and Species Variation of the Polyether Toxins, Azaspiracids, in Shellfish". Environmental Science & Technology 37 (14): 3078–84. doi:10.1021/es020246z. PMID 12901653. Bibcode: 2003EnST...37.3078F. 
  15. ↑ Amzil, Zouher; Sibat, Manoella; Royer, Florence; Savar, Véronique (2008). "First report on azaspiracid and yessotoxin groups detection in French shellfish". Toxicon 52 (1): 39–48. doi:10.1016/j.toxicon.2008.05.006. PMID 18573273. https://archimer.ifremer.fr/doc/00000/4560/. 
  16. ↑ Elgarch, Adra; Vale, Paulo; Rifai, Saida; Fassouane, Aziz (2008). "Detection of Diarrheic Shellfish Poisoning and Azaspiracids Toxins in Moroccan Mussels: Comparison of LC-MS Method with the Commercial Immunoassay Kit". Marine Drugs 6 (4): 587–94. doi:10.3390/md6040587. PMID 19172196. 
  17. ↑ Taleb, H.; Vale, P.; Amanhir, R.; Benhadouch, A.; Sagou, R.; Chafik, A. (2006). "First detection of azaspiracids in mussels in north west Africa". Journal of Shellfish Research 25 (3): 1067–70. doi:10.2983/0730-8000(2006)25[1067:FDOAIM2.0.CO;2]. 
  18. ↑ Álvarez, Gonzalo; Uribe, Eduardo; Ávalos, Paulo; Mariño, Carmen; Blanco, Juan (2010). "First identification of azaspiracid and spirolides in Mesodesma donacium and Mulinia edulis from Northern Chile". Toxicon 55 (2–3): 638–41. doi:10.1016/j.toxicon.2009.07.014. PMID 19631679. 
  19. ↑ López-Rivera, A.; o’Callaghan, K.; Moriarty, M.; o’Driscoll, D.; Hamilton, B.; Lehane, M.; James, K.J.; Furey, A. (2010). "First evidence of azaspiracids (AZAs): A family of lipophilic polyether marine toxins in scallops (Argopecten purpuratus) and mussels (Mytilus chilensis) collected in two regions of Chile". Toxicon 55 (4): 692–701. doi:10.1016/j.toxicon.2009.10.020. PMID 19852974. 
  20. ↑ Ueoka, Reiko; Ito, Akihiro; Izumikawa, Miho; Maeda, Satoko; Takagi, Motoki; Shin-Ya, Kazuo; Yoshida, Minoru; Van Soest, Rob. W.M. et al. (2009). "Isolation of azaspiracid-2 from a marine sponge Echinoclathria sp. As a potent cytotoxin". Toxicon 53 (6): 680–4. doi:10.1016/j.toxicon.2009.02.008. PMID 19233223. 
  21. ↑ Torgersen, Trine; Bremnes, Nanna Bruun; Rundberget, Thomas; Aune, Tore (2008). "Structural confirmation and occurrence of azaspiracids in Scandinavian brown crabs (Cancer pagurus)". Toxicon 51 (1): 93–101. doi:10.1016/j.toxicon.2007.08.008. PMID 17936866. 
  22. ↑ Akselman, Rut; Negri, Rubén M. (2012). "Blooms of Azadinium cf. Spinosum Elbrächter et Tillmann (Dinophyceae) in northern shelf waters of Argentina, Southwestern Atlantic". Harmful Algae 19: 30–8. doi:10.1016/j.hal.2012.05.004. 
  23. ↑ Tillmann, Urban; Elbrächter, Malte; John, Uwe; Krock, Bernd (2011). "A new non-toxic species in the dinoflagellate genus Azadinium:A. Poporumsp. Nov". European Journal of Phycology 46: 74–87. doi:10.1080/09670262.2011.556753. 
  24. ↑ Tillmann, Urban; Elbrächter, Malte; John, Uwe; Krock, Bernd; Cembella, Allan (2010). "Azadinium obesum (Dinophyceae), a new nontoxic species in the genus that can produce azaspiracid toxins". Phycologia 49 (2): 169. doi:10.2216/PH09-35.1. https://epic.awi.de/id/eprint/20337/1/Til2009d.pdf. 
  25. ↑ Salas, Rafael; Tillmann, Urban; John, Uwe; Kilcoyne, Jane; Burson, Amanda; Cantwell, Caoimhe; Hess, Philipp; Jauffrais, Thierry et al. (2011). "The role of Azadinium spinosum (Dinophyceae) in the production of azaspiracid shellfish poisoning in mussels". Harmful Algae 10 (6): 774–83. doi:10.1016/j.hal.2011.06.010. https://archimer.ifremer.fr/doc/00049/16049/15836.pdf. 
  26. ↑ Jauffrais, Thierry; Marcaillou, Claire; Herrenknecht, Christine; Truquet, Philippe; Séchet, Véronique; Nicolau, Elodie; Tillmann, Urban; Hess, Philipp (2012). "Azaspiracid accumulation, detoxification and biotransformation in blue mussels (Mytilus edulis) experimentally fed Azadinium spinosum". Toxicon 60 (4): 582–95. doi:10.1016/j.toxicon.2012.04.351. PMID 22575282. https://archimer.ifremer.fr/doc/00088/19877/17566.pdf. 
  27. ↑ Twiner, Michael J.; Doucette, Gregory J.; Rasky, Andrew; Huang, Xi-Ping; Roth, Bryan L.; Sanguinetti, Michael C. (2012). "Marine Algal Toxin Azaspiracid is an Open-State Blocker of hERG Potassium Channels". Chemical Research in Toxicology 25 (9): 1975–84. doi:10.1021/tx300283t. PMID 22856456. 
  28. ↑ 28.0 28.1 Furey, Ambrose; O'Doherty, Sinead; O'Callaghan, Keith; Lehane, Mary; James, Kevin J. (2010). "Azaspiracid poisoning (AZP) toxins in shellfish: Toxicological and health considerations". Toxicon 56 (2): 173–90. doi:10.1016/j.toxicon.2009.09.009. PMID 20026101. 
  29. ↑ Mcmahon, T.; Silke, J. (1996). "Winter toxicity of unknown aetiology in mussels". Harmful Algae News 14: 2. 
  30. ↑ Klontz, Karl C.; Abraham, A; Plakas, S. M.; Dickey, R. W. (2009). "Mussel-Associated Azaspiracid Intoxication in the United States". Annals of Internal Medicine 150 (5): 361. doi:10.7326/0003-4819-150-5-200903030-00023. PMID 19258569. 
  31. ↑ Dounay, A. B.; Forsyth. C. J. Org. Lett., 2001, 3, 975-978
  32. ↑ Nicolaou, K. C.; Chen, David Y.-K.; Li, Yiwei; Qian, Wenyuan; Ling, Taotao; Vyskocil, Stepan; Koftis, Theocharis V.; Govindasamy, Mugesh et al. (2003). "Total Synthesis of the Proposed Azaspiracid-1 Structure, Part 2: Coupling of the C1–C20, C21–C27, and C28–C40 Fragments and Completion of the Synthesis". Angewandte Chemie International Edition 42 (31): 3649–53. doi:10.1002/anie.200351826. PMID 12916037. 
  33. ↑ Nicolaou, K. C.; Li, Yiwei; Uesaka, Noriaki; Koftis, Theocharis V.; Vyskocil, Stepan; Ling, Taotao; Govindasamy, Mugesh; Qian, Wenyuan et al. (2003). "Total Synthesis of the Proposed Azaspiracid-1 Structure, Part 1: Construction of the Enantiomerically Pure C1–C20, C21–C27, and C28–C40 Fragments". Angewandte Chemie International Edition 42 (31): 3643–8. doi:10.1002/anie.200351825. PMID 12916036. 
  34. ↑ Nguyen, S.; Geisler, L. K.; Forsyth, C. J. Org. Lett. 2004, 6, 4159-4162.
  35. ↑ Nicolaou, K. C.; Koftis, Theocharis V.; Vyskocil, Stepan; Petrovic, Goran; Ling, Taotao; Yamada, Yoichi M. A.; Tang, Wenjun; Frederick, Michael O. (2004). "Structural Revision and Total Synthesis of Azaspiracid-1, Part 2: Definition of the ABCD Domain and Total Synthesis". Angewandte Chemie International Edition 43 (33): 4318–24. doi:10.1002/anie.200460696. PMID 15368381. 
  36. ↑ Nicolaou, K. C.; Vyskocil, Stepan; Koftis, Theocharis V.; Yamada, Yoichi M. A.; Ling, Taotao; Chen, David Y.-K.; Tang, Wenjun; Petrovic, Goran et al. (2004). "Structural Revision and Total Synthesis of Azaspiracid-1, Part 1: Intelligence Gathering and Tentative Proposal". Angewandte Chemie International Edition 43 (33): 4312–8. doi:10.1002/anie.200460695. PMID 15368380. 
  37. ↑ Kenton, N.; Adu-Ampratwum, D.; Okumu, A. A.; McCarron, P.; Kilcoyne, J.; Rise, F.; Wilkins, A. L.; Miles, C. O. et al. (2017). "Stereochemical Definition of the Natural Product (6R ,10R ,13R, 14R ,16R ,17R ,19S ,20S ,21R ,24S ,25S ,28S ,30S ,32R ,33R ,34R ,36S ,37S ,39R )-Azaspiracid-3 by Total Synthesis and Comparative Analyses". Angew. Chem. Int. Ed. 57 (3): 810–813. doi:10.1002/anie.201711008. PMID 29193497. 



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