Antillatoxin

Last updated
Antillatoxin
Antillatoxin.svg
3D structure Antillatoxin large.png
Three-dimensional representation of antillatoxin
Names
IUPAC name
(6S,9S,14R,15R)-7,9,14-Trimethyl-13-methylidene-6-propan-2-yl-15-[(2E,4E)-4,6,6-trimethylhepta-2,4-dien-2-yl]-1-oxa-4,7,10-triazacyclopentadecane-2,5,8,11-tetrone
Other names
ATX
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
PubChem CID
  • InChI=1S/C27H43N3O5/c1-16(2)23-25(33)28-15-22(32)35-24(17(3)12-11-13-27(7,8)9)19(5)18(4)14-21(31)29-20(6)26(34)30(23)10/h11-13,16,19-20,23-24H,4,14-15H2,1-3,5-10H3,(H,28,33)(H,29,31)/b13-11+,17-12+/t19-,20+,23+,24+/m1/s1
    Key: TYCMYIZCBRIDDR-GHGXTVDISA-N
  • InChI=1/C27H43N3O5/c1-16(2)23-25(33)28-15-22(32)35-24(17(3)12-11-13-27(7,8)9)19(5)18(4)14-21(31)29-20(6)26(34)30(23)10/h11-13,16,19-20,23-24H,4,14-15H2,1-3,5-10H3,(H,28,33)(H,29,31)/b13-11+,17-12+/t19-,20+,23+,24+/m1/s1
    Key: TYCMYIZCBRIDDR-GHGXTVDIBQ
  • C[C@H]1[C@@H](OC(=O)CNC(=O)[C@@H](N(C(=O)[C@@H](NC(=O)CC1=C)C)C)C(C)C)/C(=C/C=C/C(C)(C)C)/C
Properties
C28H45N3O5
Molar mass 503.674
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Antillatoxin (ATX) is a potent lipopeptide neurotoxin produced by the marine cyanobacterium Lyngbya majuscula . ATX activates voltage-gated sodium channels, which can cause cell depolarisation, NMDA-receptor overactivity, excess calcium influx and neuronal necrosis.

Contents

Sources

Antillatoxin is found in the venom of the marine cyanobacterium Lyngbya majuscula . The filamentous cyanobacterium grows on seagrass, macroalgae, and corals up to 30m deep in tropical and subtropical regions throughout the world. [1]

Structure

The three dimensional NMR study of this toxin showed that it consists of a tripeptide glycine-N-methylvaline-alanine, a hydroxycarboxylic acid and a 9-t-butyl-6,8-dimethyl-6,8-diene attached to the C5 atom of the cyclic peptide backbone. [2] [3]

Analogs

There are three known analogous structures of ATX which have different toxicity: antillatoxin B (8-demethyl-antillatoxin) and DH-ATX (8-demethyl-8,9-dihydro-antillatoxin), [4] [5] and various stereoisomers of antillatoxin A. These various structures have been found to be less toxic than antillatoxin A. Synthetic versions of antillatoxin have been produced with conformational variations of the lipophilic side chain. All of these structures drastically changed the toxins activity. Structures where the C7-C8=C9 bond angle was closer to 180o showed lower levels of toxicity in cell cultures. Structures that added a bulky side group to the C5 position also showed dramatic decreases in toxicity, including loss of activity. [6]

Synthesis

The figure below shows the first total synthesis of antillatoxin by Yokokawa et al. in 1998. (2E,4E)-2,4,6,6-Tetramethyl-2,4-heptadien-1-ol was transformed using a stereoselective aldol reaction, followed by the addition of a triethylsilyl protecting group. This allowed for cleavage of the chiral auxiliary of the ester. TPAP oxidation followed by Still’s olefination and protonation leads to the lactone. After transformation into the phenylselenyl derivative, alkaline cleavage, allyl esterification and coupling with the tripeptide yields the ester. Oxidation leads to the linear product, which is transformed into antillatoxin by deprotection at the N and C terminals and macrolactimization with DPPA. [7]

Chemical Synthesis of Antillatoxin Antillatoxin Synthesis.jpg
Chemical Synthesis of Antillatoxin

Target

Antillatoxin is a sodium channel gating modifier with special efficacy in cells expressing rNav1.2, rNav1.4 and rNav1.5 α subunits. [5] It is suggested that ATX preferentially binds to the voltage-gated sodium channel in the inactivated state. [5] The specific site of interaction of this neurotoxin is not yet known, however there is an allosteric interaction between ATX and brevetoxin (PbTx) at site 5 of the α subunit, which indicates that the neurotoxin site for ATX is topologically close and/or conformationally coupled to neurotoxin site 5. [8] Additionally, sites 1, 2, 3, 5 and 7 were ruled out as possible binding sites.

Changing the tert-butyl-substituted diene groups reduced toxicity, which proves that the twisted shape of these groups plays a critical role in the degree of neurotoxicity of ATX. [9]

Mode of action

Antillatoxin activates voltage-gated sodium channels, thus increasing sodium influx into the cell. [8] [10] It is hypothesized that ATX creates the increase in sodium influx by altering the voltage-gating properties of the channel. The toxin might change the voltage dependence of inactivation or augment the rate of recovery from inactivation. [5] The effect is concentration dependent, with similar potency for the rNav1.2, rNav1.4 and rNav1.5 α-subunit types of sodium channels. [5]

Antillatoxin-induced cytotoxicity is thought to occur through excessive activation of NMDA receptors by increased sodium influx, leading to excess calcium influx and necrosis. [8] The exact mechanism is still unclear, as antillatoxin’s effect on the membrane potential is not sufficient to relieve the NMDA receptor block by magnesium. [10]

Aside from toxic effects, ATX seems to enhance neurite outgrowth in developing immature neurons, depending on sodium influx, NMDA receptor activity, voltage-gated calcium channels and the calmodulin-kinase pathway. [10]

Toxicity

The toxin has been implicated in cases of respiratory irritation, inflammation of the eye and severe contact dermatitis in fishermen. [11] Antillatoxin is a very potent neurotoxin, [2] although exact toxicity differs between species. The lethal concentration LC50 is about 0.1 μM for goldfish, [4] making it the most potent toxin known for goldfish after brevetoxin. [2] It can be cytotoxic to single cerebellar granule cells at concentrations as low as 20 nM in rats [12] but more typically at 50 nM. [3]

Morphological features of antillatoxin-induced neuronal toxicity are swelling of neuronal somata, thinning of neurites and blebbing of neurite membranes. [12]

Drug Interactions

Cytotoxicity can be blocked by noncompetitive NMDA antagonists, such as dextrorphan and MK-801. [12] These compounds are only effective when present at the same time as the toxin, as opposed to post-exposure. Tetrodotoxin, a sodium channel antagonist, was found to prevent the sodium and calcium influxes caused by antillatoxin. [13] Other voltage gated sodium channel antagonists also inhibit the effects of antillatoxin, such as lidocaine, lamotrigine, phenytoin, carbamazepine, riluzole, and SKA-19. Riluzole, SKA-19, carbamazepine, and lamotrigine were capable of near complete inhibition of membrane depolarization, based on their concentration. [14]

Antillatoxin itself is an allosteric agonist for the action of batrachotoxin, and becomes even more effective when combined with brevetoxin. [13]

Related Research Articles

Neurotoxin Toxin harmful to nervous tissue

Neurotoxins are toxins that are destructive to nerve tissue. Neurotoxins are an extensive class of exogenous chemical neurological insults that can adversely affect function in both developing and mature nervous tissue. The term can also be used to classify endogenous compounds, which, when abnormally contacted, can prove neurologically toxic. Though neurotoxins are often neurologically destructive, their ability to specifically target neural components is important in the study of nervous systems. Common examples of neurotoxins include lead, ethanol, glutamate, nitric oxide, botulinum toxin, tetanus toxin, and tetrodotoxin. Some substances such as nitric oxide and glutamate are in fact essential for proper function of the body and only exert neurotoxic effects at excessive concentrations.

<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).

Poneratoxin is a paralyzing neurotoxic peptide made by the bullet ant Paraponera clavata. It prevents inactivation of voltage gated sodium channels and therefore blocks the synaptic transmission in the central nervous system. Specifically, poneratoxin acts on voltage gated sodium channels in skeletal muscle fibers, causing paralysis, and nociceptive fibers, causing pain. It is rated as a 4 plus on the Schmidt sting pain index, the highest possible rating with that system, and its effects can cause waves of pain up to twelve hours after a single sting. Schmidt describes it as "pure, intense, brilliant pain...like walking over flaming charcoal with a three-inch nail embedded in your heel." It is additionally being studied for its uses in biological insecticides.

<i>Moorea producens</i> Species of bacterium

Moorea producens is a species of filamentous cyanobacteria in the genus Moorea, including tropical marine strains formerly classified as Lyngbya majuscula due to morphological resemblance but separated based on genetic evidence. Moorea producens grows on seagrass and is one of the causes of the human skin irritation seaweed dermatitis. It is known as fireweed in Australia and stinging limu in Hawaii.

Brevetoxin Class of chemical compounds produced naturally

Brevetoxin (PbTx), or brevetoxins, are a suite of cyclic polyether compounds produced naturally by a species of dinoflagellate known as Karenia brevis. Brevetoxins are neurotoxins that bind to voltage-gated sodium channels in nerve cells, leading to disruption of normal neurological processes and causing the illness clinically described as neurotoxic shellfish poisoning (NSP).

Neurotoxic shellfish poisoning 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.

Lyngbyatoxin-a 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.

<i>Lyngbya majuscula</i> Species of bacterium

Lyngbya majuscula is a species of filamentous cyanobacteria in the genus Lyngbya. It is named after the Dane Hans Christian Lyngbye.

Neosaxitoxin 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.

Dragomabin Chemical compound

Dragomabin is a bio-active isolate of marine cyanobacteria, Lyngbya majuscula, which has been shown to have good antimalarial activity.

Curacin A is a hybrid polyketide synthase (PKS)/nonribosomal peptide synthase (NRPS) derived natural product produced isolated from the cyanobacterium Lyngbya majuscula. Curacin A belongs to a family of natural products including jamaicamide, mupirocin, and pederin that have an unusual terminal alkene. Additionally, Curacin A contains a notable thiazoline ring and a unique cyclopropyl moiety, which is essential to the compound's biological activity. Curacin A has been characterized as potent antiproliferative cytotoxic compound with notable anticancer activity for several cancer lines including renal, colon, and breast cancer. Curacin A has been shown to interact with colchicine binding sites on tubulin, which inhibits microtubule polymerization, an essential process for cell division and proliferation.

Blood-depressing substance-1 (BDS-1), also known as kappa-actitoxin-Avd4a, is a polypeptide found in the venom of the snakelocks anemone Anemonia sulcata. BDS-1 is a neurotoxin that modulates voltage-dependent potassium channels, in particular Kv3-family channels, as well as certain sodium channels. This polypeptide belongs to the sea anemone type 3 toxin peptide family.

Kalkitoxin, a toxin derived from the cyanobacterium Lyngbya majuscula, induces NMDA receptor mediated neuronal necrosis, blocks voltage-dependent sodium channels, and induces cellular hypoxia by inhibiting the electron transport chain (ETC) complex 1.

Gambierol is a marine polycyclic ether toxin which is produced by the dinoflagellate Gambierdiscus toxicus. Gambierol is collected from the sea at the Rangiroa Peninsula in French Polynesia. The toxins are accumulated in fish through the food chain and can therefore cause human intoxication. The symptoms of the toxicity resemble those of ciguatoxins, which are extremely potent neurotoxins that bind to voltage-sensitive sodium channels and alter their function. These ciguatoxins cause ciguatera fish poisoning. Because of the resemblance, there is a possibility that gambierol is also responsible for ciguatera fish poisoning. Because the natural source of gambierol is limited, biological studies are hampered. Therefore, chemical synthesis is required.

ATX-II, also known as neurotoxin 2, Av2, Anemonia viridis toxin 2 or δ-AITX-Avd1c, is a neurotoxin derived from the venom of the sea anemone Anemonia sulcata. ATX-II slows down the inactivation of different voltage-gated sodium channels, including Nav1.1 and Nav1.2, thus prolonging action potentials.

Beta-mammal toxin Cn2, also known as Cn2 toxin, is a single chain β-scorpion neurotoxic peptide and the primary toxin in the venom of the Centruroides noxius Hoffmann scorpion. The toxin specifically targets mammalian Nav1.6 voltage-gated sodium channels (VGSC).

Hoiamides Chemical compound

The hoiamides are a class of small molecules recently characterized from isolations of secondary metabolites of cyanobacteria that feature a triheterocyclic system. Hoiamide A and B are cyclic while hoiamide C and D are linear. Hoiamide A and B demonstrate neurotoxicity by acting on mammalian voltage gated sodium channels, while hoiamide D shows inhibition of the p53/MDM2 complex. The hoiamides are promising therapeutic targets, making their total synthesis an attractive feat.


N58A is a peptide depressant β-neurotoxin found in the venom of certain East Asian scorpions. The toxin affects voltage-gated sodium channels, specifically Nav1.8 & Nav1.9 channels.

Mussel toxic peptide (MTP) is a marine biotoxin that can be found in mussels of the species Mytilus edulis that are contaminated by mycotoxins produced by fungi of the genus Trichoderma. MTP is a voltage-gated sodium channel blocker, which has a mild effect on voltage-gated potassium channels.

Versutoxin

Delta hexatoxin Hv1 is a neurotoxic component found in the venom of the Australian funnel web spider.

References

  1. ↑ Osborne, Nicholas J. T.; Webb, Penny M.; Shaw, Glen R. (2001-11-01). "The toxins of Lyngbya majuscula and their human and ecological health effects". Environment International. 27 (5): 381–392. doi:10.1016/S0160-4120(01)00098-8. PMID   11757852.
  2. 1 2 3 Orjala, Jimmy; Nagle, Dale G.; Hsu, Victor; Gerwick, William H. (1995-08-01). "Antillatoxin: An Exceptionally Ichthyotoxic Cyclic Lipopeptide from the Tropical Cyanobacterium Lyngbya majuscula". Journal of the American Chemical Society. 117 (31): 8281–8282. doi:10.1021/ja00136a031. ISSN   0002-7863.
  3. 1 2 Inoue, Masayuki (2014-01-01). "Chemical construction and structural permutation of neurotoxic natural product, antillatoxin: importance of the three-dimensional structure of the bulky side chain". Proceedings of the Japan Academy, Series B. 90 (2): 56–66. Bibcode:2014PJAB...90...56I. doi:10.2183/pjab.90.56. PMC   3948940 . PMID   24522155.
  4. 1 2 Nogle, Lisa M.; Okino, Tatsufumi; Gerwick, William H. (2001-07-01). "Antillatoxin B, a Neurotoxic Lipopeptide from the Marine Cyanobacterium Lyngbya majuscula". Journal of Natural Products. 64 (7): 983–985. doi:10.1021/np010107f. ISSN   0163-3864. PMID   11473443.
  5. 1 2 3 4 5 Cao, Zhengyu; Gerwick, William H.; Murray, Thomas F. (2010-12-14). "Antillatoxin is a sodium channel activator that displays unique efficacy in heterologously expressed rNav1.2, rNav1.4 and rNav1.5 alpha subunits". BMC Neuroscience. 11 (1): 154. doi:10.1186/1471-2202-11-154. ISSN   1471-2202. PMC   3009643 . PMID   21156065.
  6. ↑ Sakai, Ryuichi; Swanson, Geoffrey T. (2014-01-16). "Recent progress in neuroactive marine natural products". Natural Product Reports. 31 (2): 273–309. doi:10.1039/C3NP70083F. PMC   3955223 . PMID   24430532.
  7. ↑ Yokokawa, Fumiaki; Fujiwara, Hideyasu; Shioiri, Takayuki (1999-03-05). "Total synthesis and revision of absolute configuration of antillatoxin, an ichthyotoxic cyclic lipopeptide of marine origin". Tetrahedron Letters. 40 (10): 1915–1916. doi:10.1016/S0040-4039(99)00042-8.
  8. 1 2 3 Li, W. I.; Berman, F. W.; Okino, T.; Yokokawa, F.; Shioiri, T.; Gerwick, W. H.; Murray, T. F. (2001-06-19). "Antillatoxin is a marine cyanobacterial toxin that potently activates voltage-gated sodium channels". Proceedings of the National Academy of Sciences. 98 (13): 7599–7604. Bibcode:2001PNAS...98.7599L. doi: 10.1073/pnas.121085898 . ISSN   0027-8424. PMC   34714 . PMID   11416227.
  9. ↑ Okura, Ken; Matsuoka, Shigeru; Goto, Ryosuke; Inoue, Masayuki (2010). "The Twisted Side Chain of Antillatoxin is Important for Potent Toxicity: Total Synthesis and Biological Evaluation of Antillatoxin and Analogues". Angewandte Chemie International Edition in English. 49 (2): 329–332. doi:10.1002/anie.200905892. PMID   19998300.
  10. 1 2 3 Jabba, S. V.; Prakash, A.; Dravid, S. M.; Gerwick, W. H.; Murray, T. F. (2010-03-01). "Antillatoxin, a Novel Lipopeptide, Enhances Neurite Outgrowth in Immature Cerebrocortical Neurons through Activation of Voltage-Gated Sodium Channels". Journal of Pharmacology and Experimental Therapeutics. 332 (3): 698–709. doi:10.1124/jpet.109.161802. ISSN   1521-0103. PMC   2835437 . PMID   20026674.
  11. ↑ Dennison, W. C.; O'Neil, J. M.; Duffy, E. J.; Oliver, P. E.; Shaw, G. R. (1999). "Blooms of the cyanobacterium Lyngbya majuscula in coastal waters of Queensland, Australia". Bulletin de l'Institut Océanographique. NS19 632: 501–506. Retrieved 2015-10-12.
  12. 1 2 3 Berman, F.W.; Gerwick, W.H; Murray, T.F (1999-11-01). "Antillatoxin and kalkitoxin, ichthyotoxins from the tropical cyanobacterium Lyngbya majuscula, induce distinct temporal patterns of NMDA receptor-mediated neurotoxicity". Toxicon. 37 (11): 1645–1648. doi:10.1016/S0041-0101(99)00108-7. PMID   10482399.
  13. 1 2 Zhang, Fan; Xu, Xunxun; Li, Tingting; Liu, Zhonghua (2013-11-28). "Shellfish Toxins Targeting Voltage-Gated Sodium Channels". Marine Drugs. 11 (12): 4698–4723. doi: 10.3390/md11124698 . PMC   3877881 . PMID   24287955.
  14. ↑ Zhao, Fang; Li, Xichun; Jin, Liang; Zhang, Fan; Inoue, Masayuki; Yu, Boyang; Cao, Zhengyu (2016-02-16). "Development of a Rapid Throughput Assay for Identification of hNav1.7 Antagonist Using Unique Efficacious Sodium Channel Agonist, Antillatoxin". Marine Drugs. 14 (2): 36. doi: 10.3390/md14020036 . PMC   4771989 . PMID   26891306.
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