# 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, and is potentially genotoxic.
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 via the terpenoid pathway and indole-3-glycerol phosphate, which is an intermediate in the tryptophan biosynthesis pathway. By expressing six genes known to be necessary for Paxilline synthesis in Aspergillus oryzae, 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 by an atypical prenyltransferase enzyme.

## Sources and references

* ↑ Paxilline product page from Fermentek
* ↑ "The structure of paxilline, a tremorgenic metabolite of penicillium paxilli bainier". Tetrahedron Letters. 16 (30): 2531–2534. 1975-01-01. doi:10.1016/S0040-4039(00)75170-7. ISSN 0040-4039.
* ↑ Evans, Tim J.; Gupta, Ramesh C. (2018-01-01). "Tremorgenic Mycotoxins". Veterinary Toxicology: 1033–1041. doi:10.1016/B978-0-12-811410-0.00074-X. ISBN 9780128114100.
* ↑ Li, Guang; Gong, Jianke; Liu, Jie; Liu, Jinzhi; Li, Huahua; Hsu, Ao-Lin; Liu, Jianfeng; Xu, X.Z. Shawn (2019). "Genetic and pharmacological interventions in the aging motor nervous system slow motor aging and extend life span in C. Elegans". Science Advances. 5 (1): eaau5041. doi:10.1126/sciadv.aau5041. PMC 6314820. PMID 30613772.
* ↑ Juhng, KN; Kokate, TG; Yamaguchi, S; Kim, BY; Rogowski, RS; Blaustein, MP; Rogawski, MA (1999). "Induction of seizures by the potent K+ channel-blocking scorpion venom peptide toxins tityustoxin-K(alpha) and pandinustoxin-K(alpha)". Epilepsy Res. 34 (2–3): 177–86. doi:10.1016/S0920-1211(98)00111-9. PMID 10210033. S2CID 140209807.
* ↑ Sheehan, JJ; Benedetti, BL; Barth, AL (2009). "Anticonvulsant effects of the BK-channel antagonist paxilline". Epilepsia. 50 (4): 711–20. doi:10.1111/j.1528-1167.2008.01888.x. PMID 19054419. S2CID 14129074.
* ↑ Fyke, William; Alarcon, Juan M.; Velinov, Milen; Chadman, Kathryn K. (2021). "Pharmacological inhibition of BKCa channels induces a specific social deficit in adult C57BL6/J mice". Behavioral Neuroscience. 135 (4): 462–468. doi:10.1037/bne0000459. PMID 33734729. S2CID 232300623 – via APA PsycArticles.
* ↑ Fueki, Shuhei; Tokiwano, Tetsuo; Toshima, Hiroaki; Oikawa, Hideaki (2004-08-01). "Biosynthesis of Indole Diterpenes, Emindole, and Paxilline: Involvement of a Common Intermediate". Organic Letters. 6 (16): 2697–2700. doi:10.1021/ol049115o. ISSN 1523-7060. PMID 15281747.
* ↑ Tagami, Koichi; Liu, Chengwei; Minami, Atsushi; Noike, Motoyoshi; Isaka, Tetsuya; Fueki, Shuhei; Shichijo, Yoshihiro; Toshima, Hiroaki; Gomi, Katsuya; Dairi, Tohru; Oikawa, Hideaki (2013-01-30). "Reconstitution of Biosynthetic Machinery for Indole-Diterpene Paxilline in Aspergillus oryzae". Journal of the American Chemical Society. 135 (4): 1260–1263. doi:10.1021/ja3116636. ISSN 0002-7863. PMID 23311903.
* ↑ Thomas, William P.; Pronin, Sergey V. (2021-03-16). "New Methods and Strategies in the Synthesis of Terpenoid Natural Products". Accounts of Chemical Research. 54 (6): 1347–1359. doi:10.1021/acs.accounts.0c00809. ISSN 0001-4842. PMC 10122273. PMID 33596652.
* ↑ Liu, Chengwei; Noike, Motoyoshi; Minami, Atsushi; Oikawa, Hideaki; Dairi, Tohru (2014-01-01). "Functional analysis of a prenyltransferase gene (paxD) in the paxilline biosynthetic gene cluster". Applied Microbiology and Biotechnology. 98 (1): 199–206. doi:10.1007/s00253-013-4834-9. hdl:2115/57639. ISSN 1432-0614. PMID 23525886. S2CID 253767473.