Paxilline Explained

Paxilline is a toxic, tremorgenic diterpene indole polycyclic alkaloid molecule produced by Penicillium paxilli which was first characterized in 1975.[1] [2] Paxilline is one of a class of tremorigenic mycotoxins, is a potassium channel blocker, and is potentially genotoxic.[3]

Paxilline was found to significantly extend the lifespan, healthspan, and mobility of aged C. elegans worms, but had no such effect on young worms.[4] Paxilline was not found to induce seizures when injected intracerebroventricularly in mice[5] but paradoxically had anticonvulsant activity against picrotoxin and pentylenetetrazol seizures in mice.[6] It has also been used in mice to induce autism-like behaviors through inhibition of the BK channel.[7]

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.[8] 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.[9] 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.[10] Paxilline has also been found to be mono- or di-prenylated with DMAPP by an atypical prenyltransferase enzyme.[11]

Notes and References

  1. http://www.fermentek.com/product/paxilline Paxilline
  2. 1975-01-01. The structure of paxilline, a tremorgenic metabolite of penicillium paxilli bainier. Tetrahedron Letters. en. 16. 30. 2531–2534. 10.1016/S0040-4039(00)75170-7. 0040-4039.
  3. 2018-01-01. Tremorgenic Mycotoxins. Veterinary Toxicology. en. 1033–1041. 10.1016/B978-0-12-811410-0.00074-X . Evans . Tim J. . Gupta . Ramesh C. . 9780128114100 .
  4. 10.1126/sciadv.aau5041. Genetic and pharmacological interventions in the aging motor nervous system slow motor aging and extend life span in C. Elegans. Science Advances. 5. eaau5041. 2019. Li. Guang. Gong. Jianke. Liu. Jie. Liu. Jinzhi. Li. Huahua. Hsu. Ao-Lin. Liu. Jianfeng. Xu. X.Z. Shawn. 1. 30613772. 6314820.
  5. 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. 10.1016/S0920-1211(98)00111-9 . 10210033 . 140209807 .
  6. Sheehan . JJ . Benedetti . BL . Barth . AL. 2009 . Anticonvulsant effects of the BK-channel antagonist paxilline. Epilepsia. 50 . 4 . 711–20. 10.1111/j.1528-1167.2008.01888.x . 19054419 . 14129074 . free .
  7. 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 . 10.1037/bne0000459 . 33734729 . 232300623 . APA PsycArticles.
  8. 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. 10.1021/ol049115o. 15281747 . 1523-7060.
  9. 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. 10.1021/ja3116636. 23311903 . 0002-7863.
  10. 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. 10.1021/acs.accounts.0c00809. 33596652 . 10122273 . 0001-4842.
  11. 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. en. 98. 1. 199–206. 10.1007/s00253-013-4834-9. 23525886 . 1432-0614. 2115/57639. 253767473 . free.

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