Maitotoxin (or MTX) is an extremely powerful

biotoxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849– ...

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 natur ...

'', a

dinoflagellate The dinoflagellates (Greek δῖνος ''dinos'' "whirling" and Latin ''flagellum'' "whip, scourge") are a monophyletic group of single-celled eukaryotes constituting the phylum Dinoflagellata and are usually considered algae. Dinoflagellates are ...

species. Maitotoxin has been shown to be more than one hundred thousand times more potent than 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 mesothel ...

injection of 130 ng/kg was lethal in mice. Maitotoxin was named from the ciguateric fish ''

Ctenochaetus striatus The striated surgeonfish, ''Ctenochaetus striatus'', is a species of marine fish in the family Acanthuridae. The striated surgeonfish can reach a maximum size of 24 cm in length, but its common size is observed to be around 18 cm. Th ...

''—called "maito" in

Tahiti Tahiti (; Tahitian ; ; previously also known as Otaheite) is the largest island of the Windward group of the Society Islands in French Polynesia. It is located in the central part of the Pacific Ocean and the nearest major landmass is Austr ...

—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, although there are also ligand-gated calcium channels. Comparison tables The following tables ex ...

, 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 the flow of io ...

, similar to how

palytoxin Palytoxin, PTX or PLTX is an intense vasoconstrictor, and is considered to be one of the most poisonous non-protein substances known, second only to maitotoxin in terms of toxicity in mice. Palytoxin is a polyhydroxylated and partially unsaturat ...

turns the Na⁺/K⁺-ATPase into an ion channel. Ultimately, a

necroptosis Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell dea ...

cascade is activated, resulting in membrane blebbing and eventually

cell lysis Lysis ( ) is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ''lysate''. In molecular bio ...

. Maitotoxin can indirectly activate calcium-binding

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

calpain-1 Calpain-1 (, ''mu-calpain'', ''calcium-activated neutral protease I'') is an enzyme. This enzyme catalyses the following chemical reaction : Broad endopeptidase specificity This enzyme belongs to the peptidase family C2. See also * CAPN1 Ca ...

and

calpain-2 Calpain-2 (, ''calcium-activated neutral protease II'', ''m-calpain'', ''milli-calpain'') is an intracellular heterodimeric calcium-activated cysteine protease. This enzyme catalyses the following chemical reaction : Broad endopeptidase specifici ...

, 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, bacterium, or plant, as well as the effect on a subst ...

of maitotoxin in mice is the highest for nonprotein toxins: the

LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is the ...

is 50 ng/kg.

Molecular structure

The

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

itself is a system of 32 fused rings. It resembles large

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...

chains and it is notable because it is 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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

, 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 wa ...

molecules produced by any

organism In biology, an organism () is any living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy into groups such as multicellular animals, plants, and ...

. Maitotoxin includes 32

ether In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...

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 . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...

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 g ...

s, and 2

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

esters In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides are ...

and has an

amphipathic An amphiphile (from the Greek αμφις amphis, both, and φιλíα philia, love, friendship), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'') properties. Such a compoun ...

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 perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with a ...

Tohoku University , or is a Japanese national university located in Sendai, Miyagi in the Tōhoku Region, Japan. It is informally referred to as . Established in 1907, it was the third Imperial University in Japan and among the first three Designated National ...

Harvard University Harvard University is a private Ivy League research university in Cambridge, Massachusetts. Founded in 1636 as Harvard College and named for its first benefactor, the Puritan clergyman John Harvard, it is the oldest institution of higher le ...

and the

University of Tokyo , abbreviated as or UTokyo, is a public research university located in Bunkyō, Tokyo, Japan. Established in 1877, the university was the first Imperial University and is currently a Top Type university of the Top Global University Project by ...

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 use ...

, 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 Kyriacos Costa Nicolaou ( el, Κυριάκος Κ. Νικολάου; born July 5, 1946) is a Cypriot-American chemist known for his research in the area of natural products total synthesis. He is currently Harry C. and Olga K. Wiess Professor of ...

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 Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

pathway.

Total synthesis

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

total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes ...

although the project is currently on hold due to a 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