Paxilline
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| Category | Mycotoxins |
| Catalog number | BBF-04076 |
| CAS | 57186-25-1 |
| Molecular Weight | 435.55 |
| Molecular Formula | C27H33NO4 |
| Purity | >99% by HPLC |
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Description
A tremorgenic mycotoxin isolated from species of penicillium, acremonium and emericella. It selectively blocks high-conductance ca2+-activated potassium channels and inhibits binding to the cerebellar inositol 1,4,5-triphosphate (insp(3)) receptor.
Specification
| Storage | Store at -20°C |
| IUPAC Name | (1S,2R,5S,7R,11S,14S)-11-hydroxy-7-(2-hydroxypropan-2-yl)-1,2-dimethyl-6-oxa-23-azahexacyclo[12.10.0.02,11.05,10.016,24.017,22]tetracosa-9,16(24),17,19,21-pentaen-8-one |
| Canonical SMILES | CC12CCC3C(=CC(=O)C(O3)C(C)(C)O)C1(CCC4C2(C5=C(C4)C6=CC=CC=C6N5)C)O |
| InChI | 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 |
| InChI Key | ACNHBCIZLNNLRS-UBGQALKQSA-N |
| Source | Paxilline is a tremorgenic mycotoxin that has been found in fungus Penicillium paxilli. |
Properties
| Appearance | White Solid |
| Boiling Point | 648.8°C at 760 mmHg |
| Melting Point | 252°C |
| Density | 1.31 g/cm3 |
| Solubility | Soluble in ethanol, methanol, DMF, DMSO |
Toxicity
| Carcinogenicity | No indication of carcinogenicity to humans (not listed by IARC). |
| Mechanism Of Toxicity | Paxilline is a tremorgenic mycotoxin. Tremorgenic mycotoxins exert their toxic effects by interfering with neurotransmitter release, possibly by causing degeneration of nerve terminals. They are thought to inhibit gamma-aminobutyric acid (GABA) receptors, both pre- and postsynaptic, as well as inhibit transmitter breakdown at the GABA-T receptors. This would initially increase neurotransmitter levels, potentiating the GABA-induced chloride current, then lead to decreased levels of neurotransmitter in the synapse. In addition, paxilline inhibits presynaptic high-conductance Ca+2 activated maxi-K+ channels in the smooth muscle. Paxilline is also genotoxic and causes DNA damage. (A2976, A2993, A3026) |
Reference Reading
1. Paxilline inhibits BK channels by an almost exclusively closed-channel block mechanism
Yu Zhou, Christopher J Lingle J Gen Physiol . 2014 Nov;144(5):415-40. doi: 10.1085/jgp.201411259.
Paxilline, a tremorogenic fungal alkaloid, potently inhibits large conductance Ca(2+)- and voltage-activated K(+) (BK)-type channels, but little is known about the mechanism underlying this inhibition. Here we show that inhibition is inversely dependent on BK channel open probability (Po), and is fully relieved by conditions that increase Po, even in the constant presence of paxilline. Manipulations that shift BK gating to more negative potentials reduce inhibition by paxilline in accordance with the increase in channel Po. Measurements of Po times the number of channels at negative potentials support the idea that paxilline increases occupancy of closed states, effectively reducing the closed-open equilibrium constant, L(0). Gating current measurements exclude an effect of paxilline on voltage sensors. Steady-state inhibition by multiple paxilline concentrations was determined for four distinct equilibration conditions, each with a distinct Po. The IC50 for paxilline shifted from around 10 nM when channels were largely closed to near 10 µM as maximal Po was approached. Model-dependent analysis suggests a mechanism of inhibition in which binding of a single paxilline molecule allosterically alters the intrinsic L(0) favoring occupancy of closed states, with affinity for the closed conformation being >500-fold greater than affinity for the open conformation. The rate of inhibition of closed channels was linear up through 2 µM paxilline, with a slope of 2 × 10(6) M(-1)s(-1). Paxilline inhibition was hindered by either the bulky cytosolic blocker, bbTBA, or by concentrations of cytosolic sucrose that hinder ion permeation. However, paxilline does not hinder MTSET modification of the inner cavity residue, A313C. We conclude that paxilline binds more tightly to the closed conformation, favoring occupancy of closed-channel conformations, and propose that it binds to a superficial position near the entrance to the central cavity, but does not hinder access of smaller molecules to this cavity.
2. Paxilline Prevents the Onset of Myotonic Stiffness in Pharmacologically Induced Myotonia: A Preclinical Investigation
Werner Klingler, Karin Jurkat-Rott, Georg Wietzorrek, Scott Wearing, Frank Lehmann-Horn, Sunisa Chaiklieng, Peter Ruth, Tina Sartorius, Kerstin Hoppe Front Physiol . 2020 Nov 23;11:533946. doi: 10.3389/fphys.2020.533946.
Reduced Cl-conductance causes inhibited muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. This represents the pathomechanism of myotonia congenita. Due to the prevailing data suggesting that an increased potassium level is a main contributor, we studied the effect of a modulator of a big conductance Ca2+- and voltage-activated K+channels (BK) modulator on contraction and relaxation of slow- and high-twitch muscle specimen before and after the pharmacological induction of myotonia. Human and murine muscle specimens (wild-type and BK-/-) were exposed to anthracene-9-carboxylic acid (9-AC) to inhibit CLC-1 chloride channels and to induce myotoniain-vitro. Functional effects of BK-channel activation and blockade were investigated by exposing slow-twitch (soleus) and fast-twitch (extensor digitorum longus) murine muscle specimens or human musculus vastus lateralis to an activator (NS1608) and a blocker (Paxilline), respectively. Muscle-twitch force and relaxation times (T90/10) were monitored. Compared to wild type, fast-twitch muscle specimen of BK-/-mice resulted in a significantly decreased T90/10in presence of 9-AC. Paxilline significantly shortened T90/10of murine slow- and fast-twitch muscles as well as human vastus lateralis muscle. Moreover, twitch force was significantly reduced after application of Paxilline in myotonic muscle. NS1608 had opposite effects to Paxilline and aggravated the onset of myotonic activity by prolongation of T90/10. The currently used standard therapy for myotonia is, in some individuals, not very effective. Thisin vitrostudy demonstrated that a BK channel blocker lowers myotonic stiffness and thus highlights its potential therapeutic option in myotonia congenital (MC).
3. The functionally relevant site for paxilline inhibition of BK channels
Yu Zhou, Xiao-Ming Xia, Christopher J Lingle Proc Natl Acad Sci U S A . 2020 Jan 14;117(2):1021-1026. doi: 10.1073/pnas.1912623117.
The tremorgenic fungal alkaloid paxilline (PAX) is a commonly used specific inhibitor of the large-conductance, voltage- and Ca2+-dependent BK-type K+channel. PAX inhibits BK channels by selective interaction with closed states. BK inhibition by PAX is best characterized by the idea that PAX gains access to the channel through the central cavity of the BK channel, and that only a single PAX molecule can interact with the BK channel at a time. The notion that PAX reaches its binding site via the central cavity and involves only a single PAX molecule would be consistent with binding on the axis of the permeation pathway, similar to classical open channel block and inconsistent with the observation that PAX selectively inhibits closed channels. To explore the potential sites of interaction of PAX with the BK channel, we undertook a computational analysis of the interaction of PAX with the BK channel pore gate domain guided by recently available liganded (open) and metal-free (closed)AplysiaBK channel structures. The analysis unambiguously identified a preferred position of PAX occupancy that accounts for all previously described features of PAX inhibition, including state dependence, G311 sensitivity, stoichiometry, and central cavity accessibility. This PAX-binding pose in closed BK channels is supported by additional functional results.
Spectrum
Predicted LC-MS/MS Spectrum - 10V, Positive
Experimental Conditions
Ionization Mode: Positive
Collision Energy: 10 eV
Instrument Type: QTOF (generic), spectrum predicted by CFM-ID
Mass Resolution: 0.0001 Da
Collision Energy: 10 eV
Instrument Type: QTOF (generic), spectrum predicted by CFM-ID
Mass Resolution: 0.0001 Da
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
