Tetrodotoxin Origins

Tetrodotoxin (TTX) is a toxin lethal to humans, and found in 6 phyla of organisms within the Animalia kingdom including the Chordata, Mollusca, Echinodermata, Chaetognatha, Arthropoda and Platyhelminthes. The phylogenetic and geographical diversity of this group, along with the many similar findings of toxin origins previously attributed to macroorganisms but found to originate from microorganisms, points to the widely supported theory that TTX is produced by a bacterium.

TTXs potency has been known for thousands of years, but only recently has it been postulated to be produced from bacteria. There are many different strains of potential TTX producing bacteria in single animals; however investigations into such bacteria in lab cultures have been inconclusive. This is most likely as conditions and triggers are missing from the usual host symbiotic environment, or the strains of bacteria producing TTX cannot be cultured.

TTX has been isolated from many toxin harbouring animals, but not all. The newt Taricha granulosa has been shown to harbour TTX with negligible evidence of an associated bacterium in the digestional tract, though due to its presence in the newt it’s involvement in TTX production cannot be ruled out. The definitive way to link bacteria and TTX would be defining the biosynthetic pathways or associated genes for producing the toxin.

Further studies of Taricha torosa and T. granulosa show that the newts gain toxicity in response to a non TTX diet, which conflict with the envirionmental dietry origins of TTX bacteria symbionts in puffer fish (Takifugu niphobles). Such environmental mechanisms aren’t uncommon in marine animals.

The best way to completely confirm TTXs origin in bacterium is to find its biosynthetic pathway and understand the genetics underpinning it. However due to TTXs unique structure this has proved to be a difficult task. To this point the literature has been inconclusive on the subject. Many different enzymes could be involved in forming its structure, leading to differing and incomparable studies which slow the development of potential molecular tools for unravelling it.

Current Ideas for the pathway look at the many similar (though not so structurally unique) bacterial toxins such as phaseotoxin, cylindrospermotoxin, and the most similar, saxotoxin. Looking into the proposed biosynthetic pathways for these leads to various unproven conclusions, the most popular of which are the genes are likely clustered together on the genome, and there is likely an enzyme analogous to amidinotransferase for its essential guanium moiety, with supporting non-ribisomal peptide isynthetase and Polyketide synthases machinery similar to saxotoxin production. This pool of thought is further supported by a wealth of TTX animals being linked to saxotoxin production.

 Investigation of the pathway for this toxin is important as it will reveal novel biosynthetic reactions and enzymes. Study of the unique carbon skeleton alone will likely give rise to pathways unlike any other investigated to date.

TTXs specificity to voltage gated sodium channels makes it a good tool in neuroscience, with useful developments coming along in anaesthesia and analgesia. Current techniques for collecting TTX from livers of puffer fish or chemically creating it are low yield, expensive and, in the case of the former, damaging to the marine environment. Due to the complexity and costs of producing this molecule surely future corporate demand allow funding for investigation of the biosynthetic pathway so to allow precise genetic engineering in microbes for a cheaper price. However the range of possibilities for the pathway are so great that much work will need to be done to develop a greater foundation of comparable literature to help solve the TTX biosynthesis puzzle.

Chau, R., Kalaitzis, J. A., & Neilan, B. A. (2011). On the origins and biosynthesis of tetrodotoxin. Aquatic toxicology, 104(1), 61-72.