25 February 2019

Maitotoxin – the heavyweight of nonbiopolymeric toxins

Natural toxin

Maitotoxin – one of the largest and most toxic non-protein and non-polysaccharide molecules – is associated with ciguatera fish poisoning.

Maitotoxin (MTx) is one of the potent polyether toxins produced by the dinoflagellate Gambierdiscus toxicus and, besides ciguatoxin, is the most common toxin involved in ciguatera fish poisoning (CFP). CFP-causing agents bioaccumulate in the aquatic food chain and may finally be ingested by humans and other animals. Symptoms of CFP vary with the geographic origin of the contaminated fish and usually include diarrhea, vomiting, thermal sense inversion, pain and paresthesia. Symptoms can range from mild to severe, lasting from a few days up to years.

Figure 1: Pathway of maitotoxin upwards the food chain: From its production by G. toxicus via herbivorous and carnivorous fish up to humans.

MTx is a polyketide-derived polycyclic ether consisting of four extended fused-ring system with a molecular weight of 3422 Da, which makes it the largest nonbiopolymeric substance, which also happens to be one of the most lethal natural substances. MTx’s mode of action comprises of the activation of Ca2+-uptake processes in a vast range of cell types. Due to its diverse biological activity, MTx received much attention for its application as pharmacological tool for the elucidation of Ca2+-dependent cellular processes, including hormone secretion, programmed cell death activation and fertilization. Additionally, MTx was extensively studied because of its complex structure and mode of action. Nevertheless, the available information on the organic and biochemical synthesis as well as its biological targets is still incomplete.

Figure 2: Structure of maitotoxin. Click for larger image

SMILES: C[C@H](CC[C@@H]([C@@H]([C@H](C)C[C@H](C(=C)/C(=C/CO)/C)O)O)OS(=O)(=O)[O-])[C@H]([C@@H](C)[C@H]1[C@@H]([C@@H]([C@H]2[C@H](O1)[C@@H](C[C@]3([C@H](O2)C[C@H]4[C@H](O3)C[C@]5([C@H](O4)[C@H]([C@H]6[C@H](O5)C[C@H]([C@H](O6)[C@@H]([C@H](C[C@H]7[C@@H]([C@@H]([C@H]8[C@H](O7)C[C@H]9[C@H](O8)C[C@H]1[C@H](O9)[C@H]([C@@H]2[C@@H](O1)[C@@H]([C@H]([C@@H](O2)[C@H]1[C@@H]([C@H]([C@H]2[C@@H](O1)C[C@H]([C@@H](O2)[C@@H](C[C@H](C[C@H]1[C@@H]([C@H]([C@H]2[C@@H](O1)C[C@H]([C@@H](O2)[C@H]1[C@@H](C[C@]2([C@H](O1)[C@@H]([C@]1([C@H](O2)C[C@]2([C@H](O1)CC[C@]1([C@H](O2)C[C@]2([C@H](O1)C[C@H]1[C@H](O2)CC[C@H](O1)[C@]1([C@@H](C[C@H]2[C@](O1)(C[C@H]1[C@](O2)(CC[C@]2([C@H](O1)C[C@H]1[C@](O2)(C[C@H]2[C@H](O1)C/C=C\[C@H]1[C@H](O2)C[C@H]2[C@](O1)(C[C@]1([C@H](O2)C[C@H]2[C@](O1)(CC[C@H](O2)[C@H]([C@@H](C[C@@H](C)[C@@H](C)CC=C)O)O)C)C)C)C)C)C)C)O)C)C)C)C)C)O)C)O)O)O)O)O)O)O)O)O)O)O)O)O)OS(=O)(=O)[O-])O)O)O)O)C)C)O)O)O)O.[Na+].[Na+]

Reyes JG, Sánchez-Cárdenas C, Acevedo-Castillo W, Leyton P, López-González I, Felix R, Gandini MA, Treviño MB, Treviño CL. 2014. Maitotoxin: An Enigmatic Toxic Molecule with Useful Applications in the Biomedical Sciences. In Botana LM: Seafood and Freshwater Toxins: Pharmacology, Physiology, and Detection. 3rd Edition. CRC Press/Taylor & Francis. pp 677-694.

Gambierdiscus toxicus microscopic picture: https://en.wikipedia.org/wiki/Gambierdiscus_toxicus#/media/File:Gambierdiscus_toxicus_NOAA.png (last accessed 11/01/2019)
Drawings of fishes and human eating:
https://etc.usf.edu/clipart/16500/16570/surgeonfish2_16570.htm (last accessed 11/01/2019)
https://etc.usf.edu/clipart/11300/11375/snapper_11375.htm (last accessed 11/01/2019)
https://etc.usf.edu/clipart/11500/11506/man_11506.htm (last accessed 11/01/2019)
Maitotoxin structure: https://en.wikipedia.org/wiki/Maitotoxin#/media/File:Maitotoxin_2D_structure.svg (last accessed 11/01/2019)