Anatoxin A

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Structural formula
Structure of anatoxin A
General
Surname Anatoxin A
other names
  • 1- {9-Azabicyclo [4.2.1] non-2-en-2-yl} ethanone ( IUPAC )
  • (1 R , 6 R ) -2-acetyl-9-aza-bicyclo [4.2.1] non-2-ene
  • Anatoxin-a
Molecular formula C 10 H 15 NO
Brief description

oily liquid

External identifiers / databases
CAS number 64285-06-9
EC number 689-000-5
ECHA InfoCard 100.215.761
PubChem 431734
ChemSpider 381822
Wikidata Q3303006
properties
Molar mass 165.232 g mol −1
Physical state

liquid, as hydrochloride white powder, as fumarate light brown powder

solubility

little in water (15 mg ml −1 , fumarate)

safety instructions
GHS labeling of hazardous substances

Fumarate

06 - Toxic or very toxic

danger

H and P phrases H: 300
P: 264-301 + 310
Toxicological data

0.25 mg kg −1 ( LD 50 ,  mouse ,  ip )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Anatoxin A , also known as Very Fast Death Factor ( VFDF ), is a neurotoxic alkaloid produced by a wide variety of cyanobacteria . The toxin as a pure substance, an oily liquid at room temperature , was extracted in 1977 by John P. Devlin from a colony of the cyanobacteria Anabaena flos-aquae , NRC-44h. Anatoxin A is extremely toxic . The LD 50 value for mice after intraperitoneal administration is around 0.25 mg / kg body  weight . When ingested, it kills within a few minutes. Anatoxin A is produced in very small quantities for basic research.

Mechanism of action

Anatoxin A is an agonist of nicotinic acetylcholine receptors . It binds to neural α4β2, α4 and muscular α12βγδ receptors . In the healthy body, acetylcholine binds to postsynaptic receptors and causes a conformational change that opens the ion channel . Positive ions flow in sequence into the cell, depolarize it and can thus trigger an action potential (or a muscle contraction). Anatoxin A binds to the same receptors and causes an irreversible conformational change that permanently opens the channel. After a while, the ion channel becomes desensitive and can no longer allow cations to pass, which ultimately leads to a blockage in signal transmission. Anatoxin-a in its effect other acetylcholine receptor agonists such as similar to nicotine of tobacco , cytisine of laburnum , Epibatidin of poison dart frog and arecoline of betel nuts .

Analytics

Methods for the reliable determination of anatoxin using HPLC in combination with mass spectrometry are available for the various test materials such as water, environmental samples or the stomach contents of dogs . Adequate sample preparation is essential.

Symptoms

Symptoms of anatoxin A poisoning are loss of coordination, convulsions and ultimately death from respiratory failure. These symptoms appear remarkably quickly, which is why the English name very fast death factor (Eng .: 'very fast death factor '). Within a few minutes, cyanobacteria of the species Anabaena flos-aquae can cause muscular fasciculations and loss of coordination. B. enter the stomach of cattle (as shown experimentally on two bulls). The death of cattle from respiratory failure occurs in a period of a few minutes to an hour. When injected intraperitoneally, the toxin is fatal to mice within two to five minutes. The symptoms are twitching, muscle cramps, paralysis and finally respiratory failure.

Threat to fauna

Flamingos on Lake Bogoria in Kenya

Since its discovery, numerous cases of anatoxin A poisoning have become known. These cases affect both wild animals and farm animals that ingest water contaminated with anatoxin A. The deaths of numerous domestic dogs in New Zealand, France, the United States and Scotland over the past 20 years have been attributed to anatoxin A by analyzing stomach contents. In all cases, the dogs showed typical symptoms such as muscle cramps within a few minutes and succumbed to the poisoning in a few hours. In addition, cattle ranches in the United States, Canada and Finland have reported deaths in livestock from drinking water contaminated with anatoxin-A over the past 30 years.

In autumn 1999, around 30,000 flamingos fell victim to anatoxin A in Lake Bogoria in Kenya. Here, too, the toxin was found in the stomach contents of dead animals and in their excrement. To this day, the anatoxin A-producing cyanobacteria that occur there ensure an annual mass extinction among the flamingos, which feed on non-toxic cyanobacteria, mostly spirulina . The causative organisms occur naturally in the water of the lake and in particular in microbe mats to a small extent that grow around the warm springs in the lake bed.

history

In June 1961, samples were taken from the lake and systematically examined after the death of some cows after drinking water from the algal bloom in Burton Lake, 120 km east of Saskatoon , Saskatchewan . The toxin produced by these organisms, which can kill mice in two to five minutes, was named Very Fast Death Factor by Paul Gorham because of its rapid action . Anatoxin A as a pure substance was described in 1977. The “most reliable and efficient” method of producing anatoxin A is achieved from a slightly acidic suspension of the cyanobacteria. This solution is freeze-dried, washed out with HCl in methanol and the extract is evaporated. The residue is first washed out with benzene to remove neutral components. The residue is then dissolved in ethanol and chloroform is added to the solution . Unwanted substances fall out while the toxin remains dissolved in the chloroform. This leaves a solid that is rich in anatoxin A hydrochloride. The total synthesis of anatoxin A was achieved in 1977 from cocaine . This clarified both structure and stereochemistry. A number of cyanobacteria that can produce anatoxin A are known, for example Aphanizomenon issatschenkoi .

Basic research

Anatoxin A is used as a model in basic research to simulate diseases that are characterized by low acetylcholine values. This applies to muscular dystrophy , myasthenia gravis , Alzheimer's disease and Parkinson's disease , for example .

Anatoxin A (S)

Anatoxin A (S) ("S" for "salivary"), also produced by cyanobacteria, causes symptoms similar to anatoxin A, but is a completely different chemical compound (organophosphate) with a different mechanism of action (inhibition of acetylcholinesterase ) . Because of the similar symptoms, both compounds were initially thought to be variants of the same toxin. A differentiating criterion is that anatoxin A (S), in contrast to anatoxin A, strongly stimulates the parasympathetic nervous system . a. leads to the aforementioned salivation.

See also

literature

  • SJ Roe, RA Stockman: A two-directional approach to the anatoxin alkaloids: second synthesis of homoanatoxin and efficient synthesis of anatoxin-a. In: Chemical Communications . Number 29, August 2008, pp. 3432-3434, doi: 10.1039 / b804304c . PMID 18633513 .
  • Rick L. Danheiser, John M. Morin, Edward J. Salaski: Efficient total synthesis of (±) -anatoxin a. In: Journal of the American Chemical Society . 107, 1985, pp. 8066-8073, doi: 10.1021 / ja00312a045 .
  • S. Vlad, WB Anderson et al .: Removal of the cyanotoxin anatoxin-a by drinking water treatment processes: a review. In: Journal of water and health. Volume 12, number 4, December 2014, pp. 601–617, doi: 10.2166 / wh.2014.018 . PMID 25473970 (Review).
  • J. Osswald, S. Rellán et al .: Toxicology and detection methods of the alkaloid neurotoxin produced by cyanobacteria, anatoxin-a. In: Environment international. Volume 33, number 8, November 2007, pp. 1070-1089, doi: 10.1016 / j.envint.2007.06.003 . PMID 17673293 (Review).
  • B. Puschner, B. Hoff, ER Tor: Diagnosis of anatoxin-a poisoning in dogs from North America. In: Journal of veterinary diagnostic investigation: official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc. Volume 20, Number 1, January 2008, pp. 89-92. PMID 18182518 .
  • E. Devic, D. Li et al .: Detection of anatoxin-a (s) in environmental samples of cyanobacteria by using a biosensor with engineered acetylcholinesterases. In: Applied and environmental microbiology. Volume 68, Number 8, August 2002, pp. 4102-4106. PMID 12147513 , PMC 123992 (free full text).

Individual evidence

  1. ↑ Eberhard Breitmaier: Alkaloids. Springer-Verlag, 2008, ISBN 978-3-8348-0531-7 , p. 35 ( limited preview in the Google book search).
  2. ↑ a b c d e f J. P. Devlin, OE Edwards, PR Gorham, NR Hunter, RK Pike, B. Stavric: Anatoxin-a, a toxic alkaloid from NRC-44h . In: Canadian Journal of Chemistry . 55, 1977, pp. 1367-1371, doi : 10.1139 / v77-189 .
  3. ↑ a b c data sheet (±) -Anatoxin A fumarate from Tocris, accessed on September 22, 2018.
  4. ↑ Data sheet (+) - Anatoxin-A fumarate from Sigma-Aldrich , accessed on April 28, 2015 ( PDF ).
  5. ↑ a b W. T. Shier: Handbook of Toxinology. CRC Press, 1990, ISBN 0-8247-8374-3 , p. 560 ( limited preview in Google book search).
  6. ↑ Nobuhiro Fusetani: Marine toxin as research tools. Springer Science & Business Media, 2009, ISBN 978-3-540-87895-7 , p. 5 ( limited preview in Google book search).
  7. ^ Antonia Herrero: The Cyanobacteria. Horizon Scientific Press, 2008, ISBN 978-1-904455-15-8 , p. 162 ( limited preview in Google book search).
  8. ↑ R. Aráoz, J. Molgó, N. Tandeau de Marsac: Neurotoxic cyanobacterial toxins. In: Toxicon . Volume 56, number 5, October 2010, pp. 813-828, doi: 10.1016 / j.toxicon.2009.07.036 . PMID 19660486 (Review).
  9. ↑ HK Yen, TF Lin, PC Liao: Simultaneous detection of nine cyanotoxins in drinking water using dual solid-phase extraction and liquid chromatography-mass spectrometry. In: Toxicon. 58 (2), Aug 2011, pp. 209-218. PMID 21699910
  10. ↑ C. Rivetti, C. Gómez-Canela, S. Lacorte, C. Barata: Liquid chromatography coupled with tandem mass spectrometry to characterize trace levels of cyanobacteria and dinoflagellate toxins in suspended solids and sediments. In: Anal Bioanal Chem. 407 (5), Feb 2015, pp. 1451-1462. PMID 25619981
  11. ↑ B. Puschner, B. Hoff, ER Tor: Diagnosis of anatoxin-a poisoning in dogs from North America. In: J Vet Diagn Invest. 20 (1), Jan 2008, pp. 89-92. PMID 18182518
  12. ↑ WW Carmichael, PR Gorham, DF Biggs: Two laboratory case studies on the oral toxicity to calves of the freshwater cyanophyte (blue-green alga) Anabaena flos-aquae NRC-44-1. In: The Canadian veterinary journal. Volume 18, Number 3, March 1977, pp. 71-75. PMID 404019 , PMC 1697489 (free full text).
  13. Jump up ↑ SA Wood, AI Selwood, A. Rueckert, PT Holland, JR Milne, KF Smith, B. Smits, LF Watts, CS Cary: First report of homoanatoxin-a and associated dog neurotoxicosis in New Zealand. In: Toxicon. Volume 50, number 2, August 2007, pp. 292-301, doi: 10.1016 / j.toxicon.2007.03.025 . PMID 17517427 .
  14. ↑ M. Gugger, S. Lenoir, C. Berger, A. Ledreux, JC Druart, JF Humbert, C. Guette, C. Bernard: First report in a river in France of the benthic cyanobacterium Phormidium favosum producing anatoxin-a associated with dog neurotoxicosis. In: Toxicon. Volume 45, Number 7, June 2005, pp. 919-928, doi: 10.1016 / j.toxicon.2005.02.031 . PMID 15904687 .
  15. ↑ B. Puschner, B. Hoff, ER Tor: Diagnosis of anatoxin-a poisoning in dogs from North America. In: Journal of veterinary diagnostic investigation. Volume 20, Number 1, January 2008, pp. 89-92. PMID 18182518 .
  16. ↑ EPA Report on Anatoxin-a ( Memento of July 4, 2015 in the Internet Archive ), accessed on April 28, 2015.
  17. ↑ L. Krienitz, A. Ballot, K. Kotut, C. Wiegand, S. Pütz, JS Metcalf, GA Codd, S. Pflugmacher: Contribution of hot spring cyanobacteria to the mysterious deaths of Lesser Flamingos at Lake Bogoria, Kenya. In: FEMS microbiology ecology. Volume 43, Number 2, March 2003, pp. 141-148, doi: 10.1111 / j.1574-6941.2003.tb01053.x . PMID 19719674 .
  18. ^ Paul R. Gorham: Laboratory Studies on the Toxins Produced by Waterblooms of Blue-Green Algae. In: American Journal of Public Health and the Nations Health. 52, 1962, pp. 2100-2105, doi: 10.2105 / AJPH.52.12.2100 .
  19. ↑ HF Campell, OE Edwards, R. Kolt: Synthesis of nor-anatoxin-a and anatoxin-a . In: Canadian Journal of Chemistry . 55, 1977, pp. 1372-1379, doi : 10.1139 / v77-190 .
  20. ↑ Susanna A. Wood, John Paul Rasmussen et al: First Report of the Cyanotoxin Anatoxin-A from Aphanizomenon issatschenkoi (cyanobacteria). In: Journal of Phycology. 43, 2007, pp. 356-365, doi: 10.1111 / j.1529-8817.2007.00318.x .
  21. ↑ https://www.spektrum.de/magazin/cyanobakterielle-toxine/821423 ; accessed on September 16, 2019