Territrem B (T3D3745)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (2)XML
Targets (2)
Record Information
Version2.0
Creation Date2010-05-10 15:50:04 UTC
Update Date2014-12-24 20:26:29 UTC
Accession NumberT3D3745
Identification
Common NameTerritrem B
ClassSmall Molecule
DescriptionTerritrem B is a tremorgenic mycotoxin found in the fungus Aspergillus terreus, which has been know to contaminate rice crops. Tremorgenic mycotoxins affect central nervous system activity, with their defining characteristic being the tremors that they cause. Territrems induce this effect by inhibiting the enzyme acetylcholinesterase in peripheral nerve endings. (3, 4)
Compound Type
  • Ester
  • Ether
  • Fungal Toxin
  • Mycotoxin
  • Natural Compound
  • Organic Compound
Chemical Structure
Thumb
MOLSDF3D-SDFPDBSMILESInChI View 3D Structure
Synonyms
Synonym
4a,12a-Dihydroxy-4,4,6a,12b-tetramethyl-9-(3,4,5-trimethoxy-phenyl)-4a,6,6a,12,12a,12b-hexahydro-4H,5H-7,10-dioxa-benzo[a]anthracene-1,11-dione
Territrem b
Territreme B
Chemical FormulaC29H34O9
Average Molecular Mass526.575 g/mol
Monoisotopic Mass526.220 g/mol
CAS Registry Number70407-20-4
IUPAC Name7a,11b-dihydroxy-5a,8,8,11a-tetramethyl-3-(3,4,5-trimethoxyphenyl)-1,5a,6,7,7a,8,11,11a,11b,12-decahydro-2,5-dioxatetraphene-1,11-dione
Traditional Name7a,11b-dihydroxy-5a,8,8,11a-tetramethyl-3-(3,4,5-trimethoxyphenyl)-7,12-dihydro-6H-2,5-dioxatetraphene-1,11-dione
SMILESCOC1=CC(=CC(OC)=C1OC)C1=CC2=C(CC3(O)C(C)(CCC4(O)C(C)(C)C=CC(=O)C34C)O2)C(=O)O1
InChI IdentifierInChI=1S/C29H34O9/c1-25(2)9-8-22(30)27(4)28(25,32)11-10-26(3)29(27,33)15-17-19(38-26)14-18(37-24(17)31)16-12-20(34-5)23(36-7)21(13-16)35-6/h8-9,12-14,32-33H,10-11,15H2,1-7H3
InChI KeyInChIKey=PBXNNDFKPQPJBB-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as naphthopyrans. Naphthopyrans are compounds containing a pyran ring fused to a naphthalene moiety. Furan is a 6 membered-ring non-aromatic ring with five carbon and one oxygen atoms. Naphthalene is a polycyclic aromatic hydrocarbon made up of two fused benzene rings.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassNaphthopyrans
Sub ClassNot Available
Direct ParentNaphthopyrans
Alternative Parents
Substituents
  • Naphthopyran
  • Naphthalene
  • Anisole
  • Phenoxy compound
  • Phenol ether
  • Methoxybenzene
  • Cyclohexenone
  • Alkyl aryl ether
  • Pyranone
  • Monocyclic benzene moiety
  • Pyran
  • Benzenoid
  • Vinylogous ester
  • Cyclic alcohol
  • Heteroaromatic compound
  • Tertiary alcohol
  • Lactone
  • Ketone
  • Ether
  • Oxacycle
  • Alcohol
  • Organooxygen compound
  • Organic oxygen compound
  • Carbonyl group
  • Organic oxide
  • Hydrocarbon derivative
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic 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 Solubility0.0085 g/LALOGPS
logP2.93ALOGPS
logP2.51ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)5.5ChemAxon
pKa (Strongest Basic)-3.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area120.75 ŲChemAxon
Rotatable Bond Count4ChemAxon
Refractivity140.34 m³·mol⁻¹ChemAxon
Polarizability55.91 ųChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0a6u-0030090000-1c98ea42021270a412f52016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-054o-1060390000-7b75be247e4bd3c4e2f12016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-00kf-3090000000-f4464045dfb2f42bec3d2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-004i-0000290000-34b1c6c6edd78eecafbd2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a71-1070690000-a1ccc19aebd7d5b6484c2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00g3-4372910000-5e2ce17407e8cb6e42f22016-08-03View Spectrum
Toxicity Profile
Route of ExposureOral, dermal, inhalation, and parenteral (contaminated drugs). (6)
Mechanism of ToxicityTerritrem B is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.
MetabolismThe biotransformation of territrems involves hydroxylation and 0-demethylation. Metabolism is performed by cytochrome P-450 monooxygenases in the liver, with CYP3A4 and CYP3A5 being the major enzymes used. (3, 5)
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesTerritrem B is a tremorgenic mycotoxin found in the fungus Aspergillus terreus. (3)
Minimum Risk LevelNot Available
Health EffectsAcute exposure to cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to organophosphate pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to organophosphate pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.
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", which is characterized by muscle tremors and hyperexcitability. (2)
TreatmentIf the compound has been ingested, rapid gastric lavage should be performed using 5% sodium bicarbonate. For skin contact, the skin should be washed with soap and water. If the compound has entered the eyes, they should be washed with large quantities of isotonic saline or water. In serious cases, atropine and/or pralidoxime should be administered. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime or obidoxime), though the use of '-oximes' has been found to be of no benefit, or possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally.
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDNot Available
HMDB IDNot Available
PubChem Compound ID114734
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. Valdes JJ, Cameron JE, Cole RJ: Aflatrem: a tremorgenic mycotoxin with acute neurotoxic effects. Environ Health Perspect. 1985 Oct;62:459-63. [2867895 ]
  2. 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 ]
  3. Ling KH, Chiou CM, Tseng YL: Biotransformation of territrems by S9 fraction from rat liver. Drug Metab Dispos. 1991 May-Jun;19(3):587-95. [1680623 ]
  4. Chen JW, Luo YL, Hwang MJ, Peng FC, Ling KH: Territrem B, a tremorgenic mycotoxin that inhibits acetylcholinesterase with a noncovalent yet irreversible binding mechanism. J Biol Chem. 1999 Dec 3;274(49):34916-23. [10574966 ]
  5. Peng FC, Chang CC, Yang CY, Edwards RJ, Doehmer J: Territrems B and C metabolism in human liver microsomes: major role of CYP3A4 and CYP3A5. Toxicology. 2006 Feb 1;218(2-3):172-85. Epub 2005 Dec 5. [16337070 ]
  6. Peraica M, Domijan AM: Contamination of food with mycotoxins and human health. Arh Hig Rada Toksikol. 2001 Mar;52(1):23-35. [11370295 ]
  7. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA. 1991 Jun 26;265(24):3255-64. [2046107 ]
  8. Schell MM. Tremorgenic mycotoxin intoxication. Veterinary Medicine. 2000.
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. Acetylcholinesterase
General Function:
Serine hydrolase activity
Specific Function:
Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.
Gene Name:
ACHE
Uniprot ID:
P22303
Molecular Weight:
67795.525 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.006 uMNot AvailableBindingDB 50089616
IC500.008 uMNot AvailableBindingDB 50089616
References
  1. Ling KH, Chiou CM, Tseng YL: Biotransformation of territrems by S9 fraction from rat liver. Drug Metab Dispos. 1991 May-Jun;19(3):587-95. [1680623 ]
  2. Chen JW, Luo YL, Hwang MJ, Peng FC, Ling KH: Territrem B, a tremorgenic mycotoxin that inhibits acetylcholinesterase with a noncovalent yet irreversible binding mechanism. J Biol Chem. 1999 Dec 3;274(49):34916-23. [10574966 ]
  3. Al-Rashid ZF, Hsung RP: (+)-Arisugacin A--computational evidence of a dual binding site covalent inhibitor of acetylcholinesterase. Bioorg Med Chem Lett. 2011 May 1;21(9):2687-91. doi: 10.1016/j.bmcl.2010.12.041. Epub 2010 Dec 16. [21216144 ]
  4. Obata R, Sunazuka T, Otoguro K, Tomoda H, Harigaya Y, Omura S: Synthetic conversion of ACAT inhibitor to acetylcholinesterase inhibitor. Bioorg Med Chem Lett. 2000 Jun 19;10(12):1315-6. [10890154 ]
Target Details
2. Acetyl-CoA acetyltransferase, mitochondrial
General Function:
Metal ion binding
Specific Function:
Plays a major role in ketone body metabolism.
Gene Name:
ACAT1
Uniprot ID:
P24752
Molecular Weight:
45199.2 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50>50 uMNot AvailableBindingDB 50089616
References
  1. Obata R, Sunazuka T, Otoguro K, Tomoda H, Harigaya Y, Omura S: Synthetic conversion of ACAT inhibitor to acetylcholinesterase inhibitor. Bioorg Med Chem Lett. 2000 Jun 19;10(12):1315-6. [10890154 ]