Antillatoxin

Antillatoxin

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 (Jmol) Interactive image
ChemSpider 28287038
PubChem 10051827
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).
Infobox references

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.

Sources

Antillatoxin is found in the venom of the marine cyanobacterium Lyngbya majuscula. This cyanobacterium has a worldwide distribution throughout the tropics and subtropics in water up to 30 m depth.[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]

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.[6] 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.[7]

Mode of action

Antillatoxin activates voltage-gated sodium channels, thus increasing sodium influx into the cell.[6][8] 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.[6] This seems plausible as cytotoxicity can be prevented by either tetrodotoxin[6] or NMDA-receptor antagonists if administered early after exposure.[9] Yet 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.[8]

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.[8]

Antillatoxin increases the binding affinity of voltage-gated sodium channels for Batrachotoxin at site 5 in an allosteric way, possibly by inducing a conformational change favourable for Batrachotoxin binding.[6]

Toxicity

The toxin has been implicated in cases of respiratory irritation, inflammation of the eye and severe contact dermatitis in fishermen.[10] 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[9] 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.[9]

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.
  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. doi:10.2183/pjab.90.56. PMC 3948940Freely accessible. 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.
  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 3009643Freely accessible. PMID 21156065.
  6. 1 2 3 4 5 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. doi:10.1073/pnas.121085898. ISSN 0027-8424. PMC 34714Freely accessible. PMID 11416227.
  7. ↑ 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.
  8. 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 2835437Freely accessible. PMID 20026674.
  9. 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.
  10. ↑ 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.
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