Paxilline is a

toxic 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 ...

, tremorgenic

diterpene Diterpenes are a class of terpenes composed of four isoprene units, often with the molecular formula C20H32. They are biosynthesized by plants, animals and fungi via the HMG-CoA reductase pathway, with geranylgeranyl pyrophosphate being a primary ...

indole Indole is an organic compound with the formula . Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole ...

polycyclic

alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...

molecule produced by '' Penicillium paxilli ''which was first characterized in 1975. Paxilline is one of a class of tremorigenic mycotoxins, is a

potassium channel blocker Potassium channel blockers are agents which interfere with conduction through potassium channels. Medical uses Arrhythmia Potassium channel blockers used in the treatment of cardiac arrhythmia are classified as class III antiarrhythmic age ...

, and is potentially

genotoxic Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with mutagenicity, all mutagens are genotoxic, but some genotoxic s ...

. Paxilline was found to significantly extend the lifespan, healthspan, and mobility of aged '' C. elegans'' worms, but had no such effect on young worms. Paxilline was not found to induce seizures when injected intracerebroventricularly in mice but paradoxically had anticonvulsant activity against picrotoxin and pentylenetetrazol seizures in mice. It has also been used in mice to induce autism-like behaviors through inhibition of the BK channel.

Biosynthesis

Paxiline biosynthesis starts with the synthesis of

geranylgeranyl pyrophosphate Geranylgeranyl pyrophosphate is an intermediate in the biosynthesis of diterpenes and diterpenoids. It is also the precursor to carotenoids, gibberellins, tocopherols, and chlorophylls. It is also a precursor to geranylgeranylated proteins, whic ...

via the

terpenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic compound, organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeabl ...

pathway and indole-3-glycerol phosphate, which is an intermediate in the

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...

biosynthesis pathway. By expressing six genes known to be necessary for Paxilline synthesis in ''

Aspergillus oryzae ''Aspergillus oryzae'', also known as , is a mold used in East Asia to saccharify rice, sweet potato, and barley in the making of alcoholic beverages such as '' sake'' and '' shōchū'', and also to ferment soybeans for making soy sauce and '' ...

'', the further steps in the biosynthesis were identified; two epoxidations and two cyclizations yield paspaline, then two oxidation reactions and a demethylation complete the synthesis. This biosynthesis is notable for its unusual stereospecific polycyclization mechanism that has not been replicated in a chemical synthesis, though other mechanisms have been devised for total synthesis of Paxilline. Paxilline has also been found to be mono- or di-

prenylated Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to ...

with DMAPP by an atypical prenyltransferase enzyme. Paxiline biosynthesis

Sources and references

{{reflist Indole alkaloids Tertiary alcohols Ketones Paxilline Diterpenes