Maitotoxin, prymnesins andzooxanthellatoxins

 

 

 

 

The structure elucidation and biological activities ofhigh molecular weight algal toxins: maitotoxin, prymnesins andzooxanthellatoxins

Michio Murata^a and   Takeshi Yasumoto^b  

Department of Chemistry, Graduate School of Science, Osaka University, 1-16 Machikaneyama, Toyonaka, Osaka, Japan

^b

Japan Food Research Laboratories, 6-11-10 Nagayama, Tama, Tokyo, Japan

Nat. Prod. Rep., 2000,17, 293-314

DOI: 10.1039/A901979K






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Maitotoxin (or MTX) is an extremely potent toxin produced by Gambierdiscus toxicus, a dinoflagellate species. Maitotoxin is so potent that it has been demonstrated that an intraperitoneal injection of 0.13 µg/kg was lethal in mice.^[1] Maitotoxin was named from the ciguateric fish Ctenochaetus striatus—called "maito" in Tahiti—from which maitotoxin was isolated for the first time. It was later shown that maitotoxin is actually produced by Gambierdiscus toxicus.

Mechanism of toxicity

Maitotoxin activates Ca²⁺ permeable, non-selective cation channels, leading to an increase in levels of cytosolic Ca²⁺ ions. It is thought that maitotoxin leads to the formation of pores on these ion channels. Ultimately, a cell death cascade is activated, resulting in membrane blebbing and eventually cell lysis.^[2] Maitotoxin is known to activate cytosolic calcium-activated proteases calpain-1 and calpain-2, contributing to necrosis.^[3] The toxicity of maitotoxin in mice is the highest for nonprotein toxins: the LD50 is 50 ng/kg.

Molecular structure

The molecule itself is a system of 32 fused rings. It resembles large fatty acid chains and it is notable because it is one of the largest and most complex non-protein, non-polysaccharide molecules produced by any organism. Maitotoxin includes 32 ether rings, 22 methyls, 28 hydroxyls, and 2 sulfuric acid esters and has an amphipathic structure.^[4][5][6] Its structure was established through analysis using nuclear magnetic resonance at Tohoku University, Harvard and the University of Tokyo in combination with mass spectrometry, and synthetic chemical methods. However, Gallimore and Spencer recently questioned the structure of maitotoxin at a single ring-junction (the J-K junction), based purely on biosynthetic considerations and their general model for marine polyether biogenesis.^[7] Nicolaou and Frederick on the other hand argue that despite this biosynthetic argument, the originally proposed structure could still be correct. ^[8] The controversy has yet to be resolved.

Biosynthesis

The core synthetic route is via a polyketide synthase pathway.^[7]

Total synthesis

Since 1996 the Nicolaou research group is involved in an effort to synthesise the molecule via total synthesis ^{[9] [10] [11] [12]} although the project is currently on hold due to a lack of funding. ^[13]

References

1. 
   

Yokoyama, A et al. (1988). "Some Chemical Properties of Maitotoxin, a Putative Calcium Channel Agonist Isolated from a Marine Dinoflagellate". J. Biochem 104 (2): 184–187. PMID 3182760.

Estacion, M and Schilling, WP (2001). "Maitotoxin-induced membrane blebbing and cell death in bovine aortic endothelial cells". BMC Physiology 1: 2. doi:10.1186/1472-6793-1-2.

Wang, K. et al. (1996). "Maitotoxin induces calpain activation in SH-SY5Y neuroblastoma cells and cerebrocortical cultures". Arch. Biochem. Biophys. 331 (2): 208–214. doi:10.1006/abbi.1996.0300. PMID 8660700.

Murata, M et al. (1994). "Structure and partial stereochemical assignments for maitotoxin, the most toxic and largest natural non-biopolymer". J. Am. Chem. Soc. 116 (16): 7098–7107. doi:10.1021/ja00095a013.

Sasaki, M et al. (1996). "The complete structure of maitotoxin, I; Configuration of the C1-C14 side chain". Angew. Chem. Int. Ed. Engl. 35 (15): 1672–1675. doi:10.1002/anie.199616721.

Kishi, Y (1998). "Complete structure of maitotoxin". Pure & Appl. Chem. 70 (2): 339–344. doi:10.1351/pac199870020339.

Gallimore AR, Spencer JB (2006). "Stereochemical Uniformity in Marine Polyether Ladders—Implications for the Biosynthesis and Structure of Maitotoxin". Angew. Chem. Int. Ed. Engl. 45 (27): 4406–4413. doi:10.1002/anie.200504284. PMID 16767782.

Nicolaou KC, Frederick MO (2007). "On the structure of maitotoxin". Angew. Chem. Int. Ed. Engl. 46 (28): 5278–82. doi:10.1002/anie.200604656. PMID 17469088.

Nicolaou, K. C., Cole, Kevin P., Frederick, Michael O., Aversa, Robert J. and Denton, Ross M. (2007), Chemical Synthesis of the GHIJK Ring System and Further Experimental Support for the Originally Assigned Structure of Maitotoxin. Angew. Chem. Int. Ed., 46: 8875–8879. doi:10.1002/anie.200703742

Chemical Synthesis of the GHIJKLMNO Ring System of Maitotoxin K. C. Nicolaou, Michael O. Frederick, Antonio C. B. Burtoloso, Ross M. Denton, Fatima Rivas, Kevin P. Cole, Robert J. Aversa, Romelo Gibe, Taiki Umezawa, and Takahiro Suzuki Journal of the American Chemical Society 2008 130 (23), 7466-7476 doi:10.1021/ja801139f

Synthesis of the ABCDEFG Ring System of Maitotoxin K. C. Nicolaou, Robert J. Aversa, Jian Jin, and Fatima Rivas Journal of the American Chemical Society 2010 132 (19), 6855-6861 doi:10.1021/ja102260q

Synthesis and Biological Evaluation of QRSTUVWXYZA′ Domains of Maitotoxin K. C. Nicolaou, Philipp Heretsch, Tsuyoshi Nakamura, Anna Rudo, Michio Murata, and Keiichi Konoki Journal of the American Chemical Society Article 2014 ASAP doi:10.1021/ja509829e

13. Chemistry's toughest total synthesis challenge put on hold by lack of funds Katrina Kramer 15 January 2015 Chemistry World http://www.rsc.org/chemistryworld/2015/01/chemistry-grandest-total-synthesis-challenge-maitotoxin-put-hold-lack-funds

Further reading

• Jones, Maitland (2004). Organic Chemistry, Third Edition. W. W. Norton & Company. ISBN 978-0-393-92408-4.

Maitotoxin

Identifiers
CAS Registry Number	59392-53-9
ChemSpider	25991548
InChI[show]
Jmol-3D images	Image
SMILES[show]
Properties
Chemical formula	C164H256O68S2Na2
Molar mass	3422 g/mol

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