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 unsaturated compound (8 double bonds) with a long carbon chain. It has water-soluble and fat-soluble parts, 40 hydroxy groups and 64 chiral centers. Due to chirality and possible double bond cis-trans isomerism, it has over 1021 alternative stereoisomers. It is thermostable, and boiling contaminated seafood does not noticeably reduce toxicity. It remains stable in aqueous solutions for prolonged periods but rapidly decomposes in acidic or alkaline solutions. It has multiple analogues such as ostreocin-D, mascarenotoxin-A and -B. Palytoxin occurs at least in tropics and subtropics where it is made by Palythoa corals and Ostreopsis dinoflagellates, or possibly by bacteria occurring in these organisms. It can be found in many more species like fish and crabs due to the process of biomagnification. It can also be found in various sponges, mussels, starfish and cnidaria. People are rarely exposed to palytoxin. Exposures have happened in people who have eaten contaminated fish and crabs, but also in aquarium hobbyists who have handled Palythoa corals incorrectly and in those who have been exposed to certain algal blooms. Palytoxin targets the sodium-potassium pump protein by locking it into a position where it allows passive transport of both sodium and potassium ions, thereby destroying the ion gradient that is essential for life. As palytoxin can affect every type of cell in the body, the symptoms can be very different for the various routes of exposure. Palytoxin's chemical structure was solved in 1981 by two research groups independently from each other. Stereochemistry was solved in 1982. Palytoxin carboxylic acid was synthesized by Yoshito Kishi and colleagues in 1989 and actual palytoxin in 1994 by Kishi and Suh.
History
Legend According to an ancient Hawaiian legend, on the island of Maui near the harbor of Hana there was a village of fishermen haunted by a curse. Upon their return from the sea, one of the fishermen would go missing. One day, enraged by another loss, the fishermen assaulted a hunchbacked hermit deemed to be the culprit of the town's misery. While ripping the cloak off the hermit the villagers were shocked because they uncovered rows of sharp and triangular teeth within huge jaws. A shark god had been caught. It was clear that the missing villagers had been eaten by the god on their journeys to the sea. The men mercilessly tore the shark god into pieces, burned him and threw the ashes into a tide pool near the harbor of Hana. Shortly after, a thick brown "moss" started to grow on the walls of the tide pool causing instant death to victims hit by spears smeared with the moss. Thus was the evil of the demon. The moss growing in the cursed tide pool became known as "limu-make-o-Hana" which literally means "seaweed of death from Hana." The Hawaiians believed that an ill curse came over them if they tried to collect the deadly "seaweed".
Discovery Palytoxin was first isolated, named and described from Palythoa toxica by Moore and Scheuer in a study published in 1971. They measured that its molar mass is approximately 3300 g/mol. They also identified it to be the substance that was probably responsible for the toxicity of P. toxica, but it was uncertain at the time if the coral also had other toxic compounds in it. It was then assessed by Walsh and Bowers that the limu-make-o-Hana was not a seaweed but a zoanthid coral, subsequently described as Palythoa toxica. Moore and Scheuer were aware of the study that Walsh and Bowers were writing.
Structure and total synthesis In 1978 by plasmadesorption the mass of the palytoxin was measured to be 2861 g/mol and that it had 8 double bonds. As palytoxin is such a large molecule, it took some time before the complete structure (including stereochemistry) was elucidated. Uemura et al. solved its planar chemical structure first and published their results in January 1981. Shortly afterwards Moore and Bartolini solved the same structure and published their results in May 1981. Forementioned groups solved the structure independently from each other. Palytoxin's stereochemistry was solved first by Moore et al. in June 1982 and then by Uemura et al. in December in a study of four parts. Palytoxin carboxylic acid was synthesized in 1989 by the group of Harvard professor Yoshito Kishi. Synthesis happened in 8 parts and then the parts were joined to form the carboxylic acid. In 1994 Kishi et al. succeeded in making the actual palytoxin from this carboxylic acid. The accomplishment of palytoxin carboxylic acid synthesis was described as "the Mount Everest of organic synthesis, the largest single molecule that anyone has ever even thought about making" by Crawford in 1989. Direct observation of the crystal structure of palytoxin was made in 2022 using microcrystal electron diffraction and an antibody named scFv. Palytoxin is found to fold into a hairpin structure which, according to simulation, would facilitate its binding with the Na+/K+-ATPase.
Occurrence Some of the organisms that contain palytoxin or its close analogues are listed below. These are either able to produce these compounds or have been found to contain them in some occasions due to bioaccumulation. Such corals are Palythoa caribeaorum, P. mammilosa, P. tuberculosa, P. toxica, P. vestitus, P. aff. margaritae, Zoanthus soanderi and Z. sociatus. Such dinoflagellates are Ostreopsis lenticularis, O. siamensis, O. mascarensis and O. ovata. Such fish are scrawled filefish, pinktail triggerfish, Ypsiscarus ovifrons, Decapterus macrosoma (shortfin scad), bluestripe herring and Epinephelus sp. Such crabs are Lophozozymus pictor, Demania reynaudii and gaudy clown crab. Certain bacteria might be able to produce palytoxin and may be the actual producers in some of the organisms listed above. Bacteria that have some evidence of palytoxin or its analogue production include Pseudomonas, Brevibacterium, Acinetobacter, Bacillus cereus, Vibrio sp. ja Aeromonas.
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