From Wikipedia, the free encyclopedia
Not to be confused with the protein
Paxillin .
Paxilline
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
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard
100.164.932
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
Y Key: ACNHBCIZLNNLRS-UBGQALKQSA-N
Y 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
C 27 H 33 N O 4
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).
Chemical compound
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]
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 .