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 chemical compounds 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 ...

indole Indole is an aromatic heterocyclic organic compound with the formula C8 H7 N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indole is widely distributed in the natural environmen ...

polycyclic

alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...

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 Mutagen, mutagenicity, all mutagens are genotoxic, but some geno ...

. Paxilline was found to significantly extend the lifespan,

healthspan Life expectancy is a statistical measure of the average time an organism is expected to live, based on the year of its birth, current age, and other demographic factors like sex. The most commonly used measure is life expectancy at birth ...

, and mobility of aged

C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...

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 Picrotoxin, also known as cocculin, is a poisonous crystalline plant compound. It was first isolated by the French pharmacist and chemist Pierre François Guillaume Boullay (1777–1869) in 1812. The name "picrotoxin" is a combination of the Gree ...

and

pentylenetetrazol Pentylenetetrazol, also known as pentylenetetrazole, leptazol, metrazol, pentetrazol (INN), pentamethylenetetrazol, Corazol, Cardiazol, Deumacard, or PTZ, is a drug formerly used as a circulatory and respiratory stimulant. High doses cause convuls ...

seizures in mice. It has also been used in mice to induce autism-like behaviors through inhibition of the

BK channel BK channels (big potassium), are large conductance calcium-activated potassium channels, also known as Maxi-K, slo1, or Kca1.1. BK channels are voltage-gated potassium channels that conduct large amounts of potassium ions (K+) across the ce ...

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, whi ...

via the

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

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 aromatic ...

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

Aspergillus oryzae ''Aspergillus oryzae'', also known as , is a filamentous fungus (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 m ...

'', 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 with

DMAPP Dimethylallyl pyrophosphate (DMAPP; or alternatively, dimethylallyl diphosphate (DMADP); also isoprenyl pyrophosphate) is an isoprenoid precursor. It is a product of both the mevalonate pathway and the MEP pathway of isoprenoid precursor biosynt ...

by an atypical prenyltransferase enzyme. Paxiline biosynthesis

Sources and references

{{reflist Indole alkaloids Tertiary alcohols Ketones

Paxilline Paxilline is a toxic, tremorgenic diterpene indole polycyclic alkaloid 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, ...

Diterpenes