Maitotoxin (MTX) is an extremely potent

toxin A toxin is a naturally occurring poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919), derived ...

produced by ''

Gambierdiscus toxicus ''Gambierdiscus toxicus'' is a species of photosynthetic unicellular eukaryote belonging to the Alveolata, part of the SAR supergroup. It is a dinoflagellate which can cause the foodborne illness ciguatera, and is known to produce several natura ...

'', a

dinoflagellate The Dinoflagellates (), also called Dinophytes, are a monophyletic group of single-celled eukaryotes constituting the phylum Dinoflagellata and are usually considered protists. Dinoflagellates are mostly marine plankton, but they are also commo ...

species. Maitotoxin has been shown to be more than one hundred thousand times as potent as VX nerve agent. Maitotoxin is so potent that it has been demonstrated that an

intraperitoneal The peritoneum is the serous membrane forming the lining of the abdominal cavity or coelom in amniotes and some invertebrates, such as annelids. It covers most of the intra-abdominal (or coelomic) organs, and is composed of a layer of mesothe ...

injection of 130 ng/kg was lethal in mice. Maitotoxin was named from the ciguateric fish '' Ctenochaetus striatus''—called "maito" in

Tahiti Tahiti (; Tahitian language, Tahitian , ; ) is the largest island of the Windward Islands (Society Islands), Windward group of the Society Islands in French Polynesia, an overseas collectivity of France. It is located in the central part of t ...

—from which maitotoxin was isolated for the first time. It was later shown that maitotoxin is actually produced by the dinoflagellate ''Gambierdiscus toxicus''.

Mechanism of toxicity

Maitotoxin activates extracellular

calcium channels A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, which are a type of calcium channel regulated by changes in membrane potential. Some calcium chan ...

, leading to an increase in levels of cytosolic Ca²⁺ ions. The exact molecular target of maitotoxin is unknown, but it has been suggested that maitotoxin binds to the plasma membrane Ca²⁺ ATPase (PMCA) and turns it into an

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...

, similar to how palytoxin turns the Na⁺/K⁺-ATPase into an ion channel. Ultimately, a necroptosis cascade is activated, resulting in membrane blebbing and eventually cell lysis. Maitotoxin can indirectly activate calcium-binding

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...

s calpain-1 and calpain-2, contributing to necrosis. The

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacteria, bacterium, or plant, as well as the effect o ...

of maitotoxin in mice is the highest for nonprotein toxins: the is 50 ng/kg.

Molecular structure

The

molecule A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...

itself is a system of 32 fused rings and is notable for being one of the largest and most complex non-

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

, non-

polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long-chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with wat ...

molecules produced by any

organism An organism is any life, living thing that functions as an individual. Such a definition raises more problems than it solves, not least because the concept of an individual is also difficult. Many criteria, few of them widely accepted, have be ...

. Maitotoxin includes 32

ether In organic chemistry, ethers are a class of compounds that contain an ether group, a single oxygen atom bonded to two separate carbon atoms, each part of an organyl group (e.g., alkyl or aryl). They have the general formula , where R and R� ...

rings, 22

methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated a ...

s, 28

hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

s, and 2

sulfuric acid Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid (English in the Commonwealth of Nations, Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen, ...

esters In chemistry, an ester is a chemical compound, compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds c ...

and has an

amphipathic In chemistry, an amphiphile (), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'', nonpolar) properties. Such a compound is called amphiphilic or amphipathic. Amphiphilic c ...

structure. Its structure was established through analysis using

nuclear magnetic resonance Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are disturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with a ...

Tohoku University is a public research university in Sendai, Miyagi, Japan. It is colloquially referred to as or . Established in 1907 as the third of the Imperial Universities, after the University of Tokyo and Kyoto University, it initially focused on sc ...

Harvard University Harvard University is a Private university, private Ivy League research university in Cambridge, Massachusetts, United States. Founded in 1636 and named for its first benefactor, the History of the Puritans in North America, Puritan clergyma ...

and the

University of Tokyo The University of Tokyo (, abbreviated as in Japanese and UTokyo in English) is a public research university in Bunkyō, Tokyo, Japan. Founded in 1877 as the nation's first modern university by the merger of several pre-westernisation era ins ...

in combination with

mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used ...

, and synthetic chemical methods. However, Andrew Gallimore and Jonathan Spencer have 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. K. C. Nicolaou and Michael Frederick argue that despite this biosynthetic argument, the originally proposed structure could still be correct. The controversy has yet to be resolved.

Biosynthesis

The molecule is produced in nature via a

polyketide synthase Polyketide synthases (PKSs) are a family of multi- domain enzymes or enzyme complexes that produce polyketides, a large class of secondary metabolites, in bacteria, fungi, plants, and a few animal lineages. The biosyntheses of polyketides share ...

pathway.

Total synthesis

Since 1996 the Nicolaou research group is involved in an effort to synthesise the molecule via

total synthesis Total synthesis, a specialized area within organic chemistry, focuses on constructing complex organic compounds, especially those found in nature, using laboratory methods. It often involves synthesizing natural products from basic, commercially ...

although as of 2015 the project is on hold due to lack of funding.''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

Mechanism of toxicity

Molecular structure

Biosynthesis

Total synthesis

See also

References

Further reading