Paxilline
Paxilline.png
Names
Preferred IUPAC name
(2R,4bS,6aS,12bS,12cR,14aS)-4b-Hydroxy-2-(2-hydroxypropan-2-yl)-12b,12c-dimethyl-5,6,6a,7,12,12b,12c,13,14,14a-decahydro-2H-[1]benzopyrano[5′,6′:6,7]indeno[1,2-b]indol-3(4bH)-one
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.164.932 Edit this at Wikidata
MeSH Paxilline
UNII
  • InChI=1S/C27H33NO4/c1-24(2,30)23-20(29)14-18-21(32-23)10-11-25(3)26(4)15(9-12-27(18,25)31)13-17-16-7-5-6-8-19(16)28-22(17)26/h5-8,14-15,21,23,28,30-31H,9-13H2,1-4H3/t15-,21-,23-,25+,26+,27+/m0/s1 checkY
    Key: ACNHBCIZLNNLRS-UBGQALKQSA-N checkY
  • InChI=1/C27H33NO4/c1-24(2,30)23-20(29)14-18-21(32-23)10-11-25(3)26(4)15(9-12-27(18,25)31)13-17-16-7-5-6-8-19(16)28-22(17)26/h5-8,14-15,21,23,28,30-31H,9-13H2,1-4H3/t15-,21-,23-,25+,26+,27+/m0/s1
    Key: ACNHBCIZLNNLRS-UBGQALKQBX
  • O=C5/C=C6/[C@]4(O)CC[C@H]3Cc2c1ccccc1[nH]c2[C@@]3([C@]4(CC[C@@H]6O[C@@H]5C(O)(C)C)C)C
Properties
C27H33NO4
Molar mass 435.56 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

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]

Paxiline biosynthesis.svg

Sources and references

  1. ^ Paxilline product page from Fermentek
  2. ^ "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.
  3. ^ "Tremorgenic Mycotoxins". Veterinary Toxicology: 1033–1041. 2018-01-01. doi:10.1016/B978-0-12-811410-0.00074-X.
  4. ^ 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: eaau5041. doi:10.1126/sciadv.aau5041. PMC 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.
  6. ^ Sheehan, JJ; Benedetti, BL; Barth, AL (2009). "Anticonvulsant effects of the BK-channel antagonist paxilline". Epilepsia. 50: 711–20.
  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 – via 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. doi:10.1021/ol049115o. ISSN 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. doi:10.1021/ja3116636. ISSN 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. doi:10.1021/acs.accounts.0c00809. ISSN 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. 98 (1): 199–206. doi:10.1007/s00253-013-4834-9. hdl:2115/57639. ISSN 1432-0614.