Aetokthonotoxin

Last updated
Aetokthonotoxin
Aetokthonotoxin.png
Names
IUPAC name
5,7-Dibromo-2-(2,3,5-tribromoindol-1-yl)-1H-indole-3-carbonitrile
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
PubChem CID
  • InChI=1S/C17H6Br5N3/c18-7-1-2-13-10(3-7)14(21)16(22)25(13)17-11(6-23)9-4-8(19)5-12(20)15(9)24-17/h1-5,24H
    Key: JXJDQKCOJBAPQM-UHFFFAOYSA-N
  • C1=CC2=C(C=C1Br)C(=C(N2C3=C(C4=C(N3)C(=CC(=C4)Br)Br)C#N)Br)Br
Properties
C17H6Br5N3
Molar mass 651.776 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Aetokthonotoxin (AETX), colloquially known as eagle toxin, is a chemical compound that was identified in 2021 as the cyanobacterial neurotoxin causing vacuolar myelinopathy (VM) in eagles in North America. [1] As the biosynthesis of aetokthonotoxin depends on the availability of bromide ions in freshwater systems and requires an interplay between the toxin-producing cyanobacterium Aetokthonos hydrillicola and the host plant it requires to live ( Hydrilla verticillata ), it took more than 25 years to identify aetokthonotoxin as the VM-inducing toxin after the disease has first been diagnosed in bald eagles in 1994. [2] The toxin cascades through the food-chain: Among other animals, it builds up in fish and waterfowl such as coots or ducks which feed on hydrilla colonized with the cyanobacterium. Aetokthonotoxin is transmitted to raptors, such as the bald eagle, as they prey on AETX poisoned animals. [3] The total synthesis of AETX was achieved in 2021, [4] the enzymatic functions of the 5 enzymes involved in AETX biosynthesis were described in 2022. [5]

Contents

Biosynthesis

The enzymatic pathway used to assemble AETX from tryptophan Aetokthonotoxin svg 1.svg
The enzymatic pathway used to assemble AETX from tryptophan

The biosynthesis of AETX and the functions of the enzymes AetA, AetB, AetD, AetE, and AetF were described in 2022. [5] AetF, a FAD-dependent halogenase, brominates L-tryptophan at the 5 position. The 5-bromo-L-tryptophan can then undergo two separate reactions. One route involves a second bromination by AetF at position 7 to yield 5,7-dibromo-L-tryptophan. This molecule then goes on to react with AetD, an iron-dependent nitrile synthase, to form an indole-3-carbonitrile derivative. The second route taken by the 5-bromo-L-tryptophan starting material involves the tryptophanase AetE, which cleaves 5-bromo-L-tryptophan into 5-bromoindole, pyruvic acid and ammonia. 5-bromoindole can then go on to react with a different FAD-dependent halogenase called AetA to form 2,3,5-tribromoindole. the 2,3,5-tribromoindole and the dibrominated-indole-3-carbonitrile then undergo biaryl coupling facilitated by the cytochrome P450 enzyme AetB to form AETX.

Toxin transmission from cyanobacteria to the bald eagle Toxin transmission from cyanobacteria to the bald eagle.jpg
Toxin transmission from cyanobacteria to the bald eagle

See also

Related Research Articles

<span class="mw-page-title-main">Tryptophan</span> Chemical compound

Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic beta carbon substituent. Tryptophan is also a precursor to the neurotransmitter serotonin, the hormone melatonin, and vitamin B3. It is encoded by the codon UGG.

<span class="mw-page-title-main">Tryptophan synthase</span> Class of enzymes

Tryptophan synthase or tryptophan synthetase is an enzyme that catalyzes the final two steps in the biosynthesis of tryptophan. It is commonly found in Eubacteria, Archaebacteria, Protista, Fungi, and Plantae. However, it is absent from Animalia. It is typically found as an α2β2 tetramer. The α subunits catalyze the reversible formation of indole and glyceraldehyde-3-phosphate (G3P) from indole-3-glycerol phosphate (IGP). The β subunits catalyze the irreversible condensation of indole and serine to form tryptophan in a pyridoxal phosphate (PLP) dependent reaction. Each α active site is connected to a β active site by a 25 Ångstrom long hydrophobic channel contained within the enzyme. This facilitates the diffusion of indole formed at α active sites directly to β active sites in a process known as substrate channeling. The active sites of tryptophan synthase are allosterically coupled.

<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 can 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">Indole-3-acetic acid</span> Chemical compound

Indole-3-acetic acid is the most common naturally occurring plant hormone of the auxin class. It is the best known of the auxins, and has been the subject of extensive studies by plant physiologists. IAA is a derivative of indole, containing a carboxymethyl substituent. It is a colorless solid that is soluble in polar organic solvents.

<span class="mw-page-title-main">Chorismic acid</span> Chemical compound

Chorismic acid, more commonly known as its anionic form chorismate, is an important biochemical intermediate in plants and microorganisms. It is a precursor for:

<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.

<span class="mw-page-title-main">Cyclopiazonic acid</span> Chemical compound

Cyclopiazonic acid (α-CPA), a mycotoxin and a fungal neurotoxin, is made by the molds Aspergillus and Penicillium. It is an indole-tetramic acid that serves as a toxin due to its ability to inhibit calcium-dependent ATPases found in the endoplasmic and sarcoplasmic reticulum. This inhibition disrupts the muscle contraction-relaxation cycle and the calcium gradient that is maintained for proper cellular activity in cells.

β-Methylamino-<small>L</small>-alanine Chemical compound

β-Methylamino-L-alanine, or BMAA, is a non-proteinogenic amino acid produced by cyanobacteria. BMAA is a neurotoxin. Its potential role in various neurodegenerative disorders is the subject of scientific research.

<span class="mw-page-title-main">Staurosporine</span> Chemical compound

Staurosporine is a natural product originally isolated in 1977 from the bacterium Streptomyces staurosporeus. It was the first of over 50 alkaloids that were discovered to share this type of bis-indole chemical structure. The chemical structure of staurosporine was elucidated by X-ray crystalography in 1994.

<span class="mw-page-title-main">Nodularin</span> Chemical compound

Nodularins are potent toxins produced by the cyanobacterium Nodularia spumigena, among others. This aquatic, photosynthetic cyanobacterium forms visible colonies that present as algal blooms in brackish water bodies throughout the world. The late summer blooms of Nodularia spumigena are among the largest cyanobacterial mass occurrences in the world. Cyanobacteria are composed of many toxic substances, most notably of microcystins and nodularins: the two are not easily differentiated. A significant homology of structure and function exists between the two, and microcystins have been studied in greater detail. Because of this, facts from microcystins are often extended to nodularins.

<span class="mw-page-title-main">Pyrrolnitrin</span> Chemical compound

Pyrrolnitrin (PRN) is a phenylpyrrole chemical used an antifungal antibiotic. Pseudomonas pyrrocinia and other Pseudomonas species produce pyrrolnitrin from tryptophan as secondary metabolite. It is believed that the antifungal properties come from inhibition of electron transport system.

<span class="mw-page-title-main">Lyngbyatoxin-a</span> Chemical compound

Lyngbyatoxin-a is a cyanotoxin produced by certain cyanobacteria species, most notably Moorea producens. It is produced as defense mechanism to ward off any would-be predators of the bacterium, being a potent blister agent as well as carcinogen. Low concentrations cause a common skin condition known as seaweed dermatitis.

<span class="mw-page-title-main">Scytonemin</span> Chemical compound

Scytonemin is a secondary metabolite and an extracellular matrix (sheath) pigment synthesized by many strains of cyanobacteria, including Nostoc, Scytonema, Calothrix, Lyngbya, Rivularia, Chlorogloeopsis, and Hyella. Scytonemin-synthesizing cyanobacteria often inhabit highly insolated terrestrial, freshwater and coastal environments such as deserts, semideserts, rocks, cliffs, marine intertidal flats, and hot springs.

Tryptophan N-monooxygenase (EC 1.14.13.125, tryptophan N-hydroxylase, CYP79B1, CYP79B2, CYP79B3) is an enzyme with systematic name L-tryptophan,NADPH:oxygen oxidoreductase (N-hydroxylating). This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Tryptophan 7-halogenase</span>

Tryptophan 7-halogenase (EC 1.14.19.9, PrnA, RebH) is an enzyme with systematic name L-tryptophan:FADH2 oxidoreductase (7-halogenating). This enzyme catalyses the following chemical reaction:

L-tryptophan—pyruvate aminotransferase is an enzyme with systematic name L-tryptophan:pyruvate aminotransferase. This enzyme catalyses the following chemical reaction

Avian vacuolar myelinopathy (AVM) is a fatal neurological disease that affects various waterbirds and raptors. It is most common in the bald eagle and American coot, and it is known in the killdeer, bufflehead, northern shoveler, American wigeon, Canada goose, great horned owl, mallard, and ring-necked duck. Avian vacuolar myelinopathy is a newly discovered disease that was first identified in the field in 1994 when dead bald eagles were found near DeGray Lake in Arkansas in the United States. Since then, it has spread to four more states and infested multiple aquatic systems including 10 reservoirs. The cause of death is lesions on the brain and spinal cord. A neurotoxin called aetokthonotoxin produced by cyanobacteria causes the disease.

Cyanopeptolins (CPs) are a class of oligopeptides produced by Microcystis and Planktothrix algae strains, and can be neurotoxic. The production of cyanopeptolins occurs through nonribosomal peptides synthases (NRPS).

<span class="mw-page-title-main">Lolitrem B</span> Chemical compound

Lolitrem B is one of many toxins produced by a fungus called Epichloë festucae var. lolii), which grows in Lolium perenne. The fungus is symbiotic with the ryegrass; it doesn't harm the plant, and the toxins it produces kill insects that feed on ryegrass. Lolitrem B is one of these toxins, but it is also harmful to mammals. The shoots and flowers of infected ryegrass have especially high concentrations of lolitrem B, and when livestock eat too much of them, they get perennial ryegrass staggers. At low doses the animals have tremors, and at higher doses they stagger, and at higher yet doses the animals become paralyzed and die. The blood pressure of the animals also goes up. The effect of the lolitrem B comes on slowly and fades out slowly, as it is stored in fat after the ryegrass is eaten. The condition is especially common in New Zealand and Australia, and plant breeders there have been trying to develop strains of fungus that produce toxins only harmful to pests, and not to mammals.

<span class="mw-page-title-main">Indoxyl sulfate</span> Chemical compound

Indoxyl sulfate, also known as 3-indoxylsulfate and 3-indoxylsulfuric acid, is a metabolite of dietary L-tryptophan that acts as a cardiotoxin and uremic toxin. High concentrations of indoxyl sulfate in blood plasma are known to be associated with the development and progression of chronic kidney disease and vascular disease in humans. As a uremic toxin, it stimulates glomerular sclerosis and renal interstitial fibrosis.

References

  1. Breinlinger, Steffen; Phillips, Tabitha J.; Haram, Brigette N.; Mareš, Jan; Yerena, José A. Martínez; Hrouzek, Pavel; Sobotka, Roman; Henderson, W. Matthew; Schmieder, Peter; Williams, Susan M.; Lauderdale, James D. (2021-03-26). "Hunting the eagle killer: A cyanobacterial neurotoxin causes vacuolar myelinopathy". Science. 371 (6536): eaax9050. doi: 10.1126/science.aax9050 . ISSN   0036-8075. PMC   8318203 . PMID   33766860.
  2. "Avian vacuolar myelinopathy". USGS National Wildlife Health Center. Archived from the original on 6 October 2014. Retrieved 24 October 2013.
  3. Birrenkott, A. H.; S. B Wilde; J. J. Hains; J. R. Fisher; T. M. Murphy; C. P. Hope; P. G. Parnell; W. W. Bowerman (2004). "Establishing a food-chain link between aquatic plant material and avian vacuolar myelinopathy in mallards (Anas platyrhynchos)". Journal of Wildlife Diseases. 40 (3): 485–492. doi: 10.7589/0090-3558-40.3.485 . PMID   15465716.
  4. Ricardo, Manuel G.; Schwark, Markus; Llanes, Dayma; Niedermeyer, Timo H. J.; Westermann, Bernhard (2021-06-03), "Total Synthesis of Aetokthonotoxin, the Cyanobacterial Neurotoxin Causing Vacuolar Myelinopathy", Chemistry – A European Journal (in German), vol. 27, no. 47, pp. 12032–12035, doi:10.1002/chem.202101848, PMC   8453946 , PMID   34081364
  5. 1 2 Adak, Sanjoy; Lukowski, April L.; Schäfer, Rebecca J. B.; Moore, Bradley S. (2022-02-10). "From Tryptophan to Toxin: Nature's Convergent Biosynthetic Strategy to Aetokthonotoxin". Journal of the American Chemical Society. 144 (7). American Chemical Society (ACS): 2861–2866. doi:10.1021/jacs.1c12778. ISSN   0002-7863. PMC   9004672 . PMID   35142504. S2CID   246702060.