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Record Information
Version2.0
Creation Date2010-05-20 16:06:57 UTC
Update Date2014-12-24 20:26:31 UTC
Accession NumberT3D3767
Identification
Common NameLolitrem B
ClassSmall Molecule
DescriptionPaspalinine is a tremorgenic mycotoxin that is produced by the fungi Neotyphodium lolii and Acremonium lolii. It may be found in contaminated cereal crops such as oats, barley, millet, corn and rice. Tremorgenic mycotoxins affect central nervous system activity and have been implicated in a number of neurologic diseases of cattle collectively known as "staggers syndromes" or “ryegrass staggers”. (5, 1, 3)
Compound Type
  • Ester
  • Ether
  • Fungal Toxin
  • Mycotoxin
  • Natural Compound
  • Organic Compound
Chemical Structure
Thumb
Synonyms
Synonym
7H-1,3Dioxino5,4:2,3oxireno4,4a1benzopyrano5,6:6,7indeno1,2-bisobenzofuro5,6-eindol-13(8H)-one
Chemical FormulaC42H55NO7
Average Molecular Mass685.889 g/mol
Monoisotopic Mass685.398 g/mol
CAS Registry Number81771-19-9
IUPAC Name22-hydroxy-1,10,10,12,12,30,30,36-octamethyl-28-(2-methylprop-1-en-1-yl)-11,24,27,29,32-pentaoxa-3-azadecacyclo[17.17.0.0²,¹⁷.0⁴,¹⁶.0⁷,¹⁵.0⁹,¹³.0²²,³⁶.0²³,²⁵.0²³,³³.0²⁶,³¹]hexatriaconta-2(17),4(16),5,7(15)-tetraen-8-one
Traditional Name22-hydroxy-1,10,10,12,12,30,30,36-octamethyl-28-(2-methylprop-1-en-1-yl)-11,24,27,29,32-pentaoxa-3-azadecacyclo[17.17.0.0²,¹⁷.0⁴,¹⁶.0⁷,¹⁵.0⁹,¹³.0²²,³⁶.0²³,²⁵.0²³,³³.0²⁶,³¹]hexatriaconta-2(17),4(16),5,7(15)-tetraen-8-one
SMILESCC(C)=CC1OC2C3OC33C(CCC4(C)C5(C)C(CC6=C5NC5=C6C6=C(C=C5)C(=O)C5C(C6)C(C)(C)OC5(C)C)CCC34O)OC2C(C)(C)O1
InChI IdentifierInChI=1S/C42H55NO7/c1-20(2)17-28-47-32-34(38(7,8)48-28)46-27-14-15-39(9)40(10)21(13-16-41(39,45)42(27)35(32)49-42)18-24-29-23-19-25-30(37(5,6)50-36(25,3)4)31(44)22(23)11-12-26(29)43-33(24)40/h11-12,17,21,25,27-28,30,32,34-35,43,45H,13-16,18-19H2,1-10H3
InChI KeyInChIKey=HGBZMCXKHKZYBF-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as kaurane diterpenoids. These are diterpene alkaloids with a structure that is based on the kaurane skeleton. Kaurane is a tetracyclic compound that arises by cyclisation of a pimarane precursor followed by rearrangement. It possesses a [3,2,1]-bicyclic ring system with C15-C16 bridge connected to C13, forming the five-membered ring D.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassPrenol lipids
Sub ClassDiterpenoids
Direct ParentKaurane diterpenoids
Alternative Parents
Substituents
  • Kaurane diterpenoid
  • Carboxylic acid ester
  • Monocarboxylic acid or derivatives
  • Carboxylic acid derivative
  • Organic oxygen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Aliphatic homopolycyclic compound
Molecular FrameworkAliphatic homopolycyclic compounds
External DescriptorsNot Available
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
SolubilityNot Available
LogPNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00022 g/LALOGPS
logP5.75ALOGPS
logP6.51ChemAxon
logS-6.5ALOGPS
pKa (Strongest Acidic)13.15ChemAxon
pKa (Strongest Basic)-3.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area102.54 ŲChemAxon
Rotatable Bond Count1ChemAxon
Refractivity189.22 m³·mol⁻¹ChemAxon
Polarizability79.94 ųChemAxon
Number of Rings10ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-000i-1000019000-66132e6b0615956284e7JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-004l-7500059000-911c3fa783cecc676d27JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-066r-9000161000-cc41dc0c2503d27116dbJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-001i-0000019000-435251defe06ce871327JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0uyi-3100059000-7d2634584c9c4489b12dJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0apl-9300052000-5c3596e8eb34d48ec6ccJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-000i-0000009000-9ac32f594a0080abf166JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0fri-2000019000-8744ed0236dca05eac59JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000f-9110035000-9bae12f1443f21c69d37JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-001i-0000009000-dd2f6c392bd7721a00f1JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-001i-0000009000-e9e00ac78c08bd2e0a36JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-001i-1120119000-9011ab8bd05cd587d4e7JSpectraViewer
Toxicity Profile
Route of ExposureOral, dermal, inhalation, and parenteral (contaminated drugs). (4)
Mechanism of ToxicityThe neurological effects of Lolitrem B are a result of its ability to inhibit large conductance calcium-activated potassium channels (BK channels). Lolitrem B binds to the alpha subunit of the BK channel, inhibiting channel potassium currents. This causes tremorgenic effects either by directly affecting channels in the muscle or by acting on channels in the central nervous system. (1, 2)
MetabolismNot Available
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesLolitrem B is a tremorgenic mycotoxin that is produced by the fungi Neotyphodium lolii and Acremonium lolii. It may be found in contaminated cereal crops such as oats, barley, millet, corn and rice. (5, 1, 3)
Minimum Risk LevelSymptoms of "ryegrass staggers" develop in livestock when concentrations exceed 2.5 ug/g in dry matter. (3)
Health EffectsTremorgenic mycotoxins affect central nervous system activity. They cause a neurological disease of cattle known as "staggers syndrome" or “ryegrass staggers”. (5, 1)
SymptomsTremorgenic mycotoxins affect central nervous system activity, inducing neurologic symptoms including mental confusion, paralysis, tremors, seizures, and death. They cause a neurological disease of cattle known as "staggers syndrome" or “ryegrass staggers”, which is characterized by impaired motor coordination, muscle tremors, hyperexcitability, convulsions, and ataxia. Additional symptoms include increased blood pressure, heart rate and respiration rate. While the neurotoxic effects of lolitrem B have a long duration, they are also reversible. (5, 1, 2, 3)
TreatmentTo control severe tremors caused by tremorgenic mycotoxins, methocarbamol should be administered. Generalized seizures may be treated with diazepam followed by methocarbamol or a barbiturate such as pentobarbital sodium. Gastric lavage should be performed and activated charcoal administered to limit further absorption of toxins. (6)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDNot Available
HMDB IDNot Available
PubChem Compound ID3086140
ChEMBL IDNot Available
ChemSpider IDNot Available
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI IDNot Available
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkNot Available
References
Synthesis ReferenceNot Available
MSDSNot Available
General References
  1. Imlach WL, Finch SC, Dunlop J, Meredith AL, Aldrich RW, Dalziel JE: The molecular mechanism of "ryegrass staggers," a neurological disorder of K+ channels. J Pharmacol Exp Ther. 2008 Dec;327(3):657-64. doi: 10.1124/jpet.108.143933. Epub 2008 Sep 18. [18801945 ]
  2. Dalziel JE, Finch SC, Dunlop J: The fungal neurotoxin lolitrem B inhibits the function of human large conductance calcium-activated potassium channels. Toxicol Lett. 2005 Mar 15;155(3):421-6. [15649626 ]
  3. Cheeke PR: Endogenous toxins and mycotoxins in forage grasses and their effects on livestock. J Anim Sci. 1995 Mar;73(3):909-18. [7608026 ]
  4. Peraica M, Domijan AM: Contamination of food with mycotoxins and human health. Arh Hig Rada Toksikol. 2001 Mar;52(1):23-35. [11370295 ]
  5. Selala MI, Daelemans F, Schepens PJ: Fungal tremorgens: the mechanism of action of single nitrogen containing toxins--a hypothesis. Drug Chem Toxicol. 1989 Sep-Dec;12(3-4):237-57. [2698801 ]
  6. Schell MM. Tremorgenic mycotoxin intoxication. Veterinary Medicine. 2000.
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Voltage-gated potassium channel activity
Specific Function:
Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+). It is also activated by the concentration of cytosolic Mg(2+). Its activation dampens the excitatory events that elevate the cytosolic Ca(2+) concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential. Plays a key role in controlling excitability in a number of systems, such as regulation of the contraction of smooth muscle, the tuning of hair cells in the cochlea, regulation of transmitter release, and innate immunity. In smooth muscles, its activation by high level of Ca(2+), caused by ryanodine receptors in the sarcoplasmic reticulum, regulates the membrane potential. In cochlea cells, its number and kinetic properties partly determine the characteristic frequency of each hair cell and thereby helps to establish a tonotopic map. Kinetics of KCNMA1 channels are determined by alternative splicing, phosphorylation status and its combination with modulating beta subunits. Highly sensitive to both iberiotoxin (IbTx) and charybdotoxin (CTX).
Gene Name:
KCNMA1
Uniprot ID:
Q12791
Molecular Weight:
137558.115 Da
References
  1. Imlach WL, Finch SC, Dunlop J, Meredith AL, Aldrich RW, Dalziel JE: The molecular mechanism of "ryegrass staggers," a neurological disorder of K+ channels. J Pharmacol Exp Ther. 2008 Dec;327(3):657-64. doi: 10.1124/jpet.108.143933. Epub 2008 Sep 18. [18801945 ]
  2. Dalziel JE, Finch SC, Dunlop J: The fungal neurotoxin lolitrem B inhibits the function of human large conductance calcium-activated potassium channels. Toxicol Lett. 2005 Mar 15;155(3):421-6. [15649626 ]