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Record Information
Version2.0
Creation Date2009-07-03 22:09:29 UTC
Update Date2014-12-24 20:25:35 UTC
Accession NumberT3D2484
Identification
Common NameTetrodotoxin
ClassSmall Molecule
DescriptionAn aminoperhydroquinazoline poison found mainly in the liver and ovaries of fishes in the order tetraodontiformes, which are eaten. Tetrodotoxin is a potent neurotoxin that is produced by bacteria (genus Pseudoalteromonas, Pseudomonas, Vibrio) and found in certain species of Tetraodontiformes (puffer fish, porcupine fish, ocean sunfish, triggerfish), from which its name is derived. It acts on the voltage-gated sodium channels of nerve cells. (1) The toxin causes paresthesia and paralysis through interference with neuromuscular conduction. Tetrodotoxin is being investigated by Wex Pharmaceuticals for the treatment of chronic and breakthrough pain in advanced cancer patients as well as for the treatment of opioid dependence.
Compound Type
  • Amide
  • Amine
  • Animal Toxin
  • Ether
  • Marine Toxin
  • Natural Compound
  • Organic Compound
  • Sodium Channel Blocker
Chemical Structure
Thumb
Synonyms
Synonym
Tectin
Tetrodin
Chemical FormulaC11H17N3O8
Average Molecular Mass319.268 g/mol
Monoisotopic Mass319.102 g/mol
CAS Registry Number4368-28-9
IUPAC Name(11S,13S)-3-amino-5,12,13,14-tetrahydroxy-14-(hydroxymethyl)-8,10-dioxa-2,4-diazatetracyclo[7.3.1.1⁷,¹¹.0¹,⁶]tetradec-3-en-4-ium-9-olate
Traditional Nametetrodotoxin
SMILES[H]C1(O)NC(=[NH2+])NC23C([H])(O)[C@]4([H])OC([O-])(OC([H])(C12[H])C4(O)CO)[C@@]3([H])O
InChI IdentifierInChI=1S/C11H16N3O8/c12-8-13-6(17)2-4-9(19,1-15)5-3(16)10(2,14-8)7(18)11(20,21-4)22-5/h2-7,15-19H,1H2,(H3,12,13,14)/q-1/p+1/t2?,3?,4?,5-,6?,7-,9?,10?,11?/m0/s1
InChI KeyInChIKey=SLBCPBUVHCASIJ-UFHSVNPDSA-O
Chemical Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as tetrodotoxins. These are compounds structurally characterized by the presence of the tetrodotoxin skeleton, which is based on 5,7-(epoxymethanooxy)quinazolin-10-olate moiety.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazanaphthalenes
Sub ClassBenzodiazines
Direct ParentTetrodotoxins
Alternative Parents
Substituents
  • Tetrodotoxin-skeleton
  • Meta-dioxane
  • Hydropyrimidine
  • 1,4,5,6-tetrahydropyrimidine
  • Monosaccharide
  • Oxane
  • Cyclic alcohol
  • Tertiary alcohol
  • Guanidine
  • Orthocarboxylic acid derivative
  • Secondary alcohol
  • Carboximidamide
  • Organic 1,3-dipolar compound
  • Azacycle
  • Propargyl-type 1,3-dipolar organic compound
  • Alkanolamine
  • Polyol
  • Oxacycle
  • Organic zwitterion
  • Alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Organic nitrogen compound
  • Organic oxygen compound
  • Primary alcohol
  • Alkoxide
  • Aliphatic heteropolycyclic compound
Molecular FrameworkAliphatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceColorless Solid (2).
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
SolubilityNot Available
LogPNot Available
Predicted Properties
PropertyValueSource
Water Solubility117.0 mg/mLALOGPS
logP0.42ALOGPS
logP-4.8ChemAxon
logS-0.5ALOGPS
pKa (Strongest Acidic)10.4ChemAxon
pKa (Strongest Basic)9.62ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count8ChemAxon
Polar Surface Area194.69 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity86.74 m3·mol-1ChemAxon
Polarizability27.83 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00di-0009000000-b7ce9130a531ed988be9View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0udr-0098000000-4cc9d0d4fc807afd209bView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000i-3091000000-da2933642dbc3ad9bc9fView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0uxr-0059000000-7c5f6a917cfd35b2ed23View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0v03-5096000000-9c701d5e323a195da9b9View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-002f-5090000000-3e75d9ff468628c782c0View in MoNA
Toxicity Profile
Route of ExposureOral (1) ; injection (sting/bite) (1)
Mechanism of ToxicityTetrodotoxin binds to what is known as site 1 of the fast voltage-gated sodium channel. Site 1 is located at the extracellular pore opening of the ion channel. The binding of any molecules to this site will temporarily disable the function of the ion channel. Saxitoxin and several of the conotoxins also bind the same site.
MetabolismThe metabolic source of tetrodotoxin is uncertain. No algal source has been identified, and until recently tetrodotoxin was assumed to be a metabolic product of the host. However, recent reports of the production of tetrodotoxin/anhydrotetrodotoxin by several bacterial species, including strains of the family Vibrionaceae, Pseudomonas sp., and Photobacterium phosphoreum, point toward a bacterial origin of this family of toxins (3).
Toxicity ValuesLD50: 334 ug/kg (Oral, Mouse) (1)
Lethal Dose25 mg for an adult human. (1)
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the treatment of chronic and breakthrough pain in advanced cancer patients as well as for the treatment of opioid dependence. Tetrodotoxin is produced by bacteria (genus Pseudoalteromonas, Pseudomonas, Vibrio) and found in certain species of Tetraodontiformes (puffer fish, porcupine fish, ocean sunfish, triggerfish), from which its name is derived. (1)
Minimum Risk LevelNot Available
Health EffectsTetrodoxin is a potent neurotoxin and produces paralysis, which may be followed by death due to respiratory failure. (1)
SymptomsSymptoms of tetrodoxin poisoning typically occur within 30 minutes of exposure and include paresthesias of the lips and tongue, sialorrhea, sweating, headache, weakness, lethargy, ataxia, uncoordination, tremor, paralysis, cyanosis, aphonia, dysphagia, seizures, dyspnoea, bronchorrhea, bronchospasm, respiratory failure, coma, and hypotension. Gastroenteric symptoms are often severe and include nausea, vomiting, diarrhoea, and abdominal pain. Cardiac arrhythmias may precede complete respiratory failure and cardiovascular collapse. (1)
TreatmentTreatment of tetrodoxin poisoning is supportive and symptomatic, with aggressive early airway management. In cases of ingestion gastric lavage and/or the administration of active charcoal may be performed. Alpha adrenergic agonists are recommended in addition to intravenous fluids to combat hypotension. (1)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB05232
HMDB IDNot Available
PubChem Compound ID443368
ChEMBL IDNot Available
ChemSpider ID391601
KEGG IDC11692
UniProt IDNot Available
OMIM ID
ChEBI ID9506
BioCyc IDNot Available
CTD IDD013779
Stitch IDTetrodotoxin
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkTetrodotoxin
References
Synthesis ReferenceNot Available
MSDST3D2484.pdf
General References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]
  2. Wikipedia. Scyllatoxin. Last Updated 5 April 2009. [Link]
  3. US Food and Drug Administration (2009). Foodborne Pathogenic Microorganisms and Natural Toxins Handbook: Tetrodotoxin. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Voltage-gated sodium channel activity
Specific Function:
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient.
Gene Name:
SCN1A
Uniprot ID:
P35498
Molecular Weight:
228969.49 Da
References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]
General Function:
Voltage-gated sodium channel activity
Specific Function:
Tetrodotoxin-resistant channel that mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which sodium ions may pass in accordance with their electrochemical gradient. Plays a role in neuropathic pain mechanisms.
Gene Name:
SCN10A
Uniprot ID:
Q9Y5Y9
Molecular Weight:
220623.605 Da
References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]
General Function:
Voltage-gated sodium channel activity
Specific Function:
This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which sodium ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant sodium channel isoform. Also involved, with the contribution of the receptor tyrosine kinase NTRK2, in rapid BDNF-evoked neuronal depolarization.
Gene Name:
SCN11A
Uniprot ID:
Q9UI33
Molecular Weight:
204919.66 Da
References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]
General Function:
Voltage-gated sodium channel activity
Specific Function:
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient.
Gene Name:
SCN2A
Uniprot ID:
Q99250
Molecular Weight:
227972.64 Da
References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]
General Function:
Voltage-gated sodium channel activity
Specific Function:
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient.
Gene Name:
SCN3A
Uniprot ID:
Q9NY46
Molecular Weight:
226291.905 Da
References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]
General Function:
Voltage-gated sodium channel activity
Specific Function:
This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. This sodium channel may be present in both denervated and innervated skeletal muscle.
Gene Name:
SCN4A
Uniprot ID:
P35499
Molecular Weight:
208059.175 Da
References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]
General Function:
Voltage-gated sodium channel activity involved in sa node cell action potential
Specific Function:
This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels.
Gene Name:
SCN5A
Uniprot ID:
Q14524
Molecular Weight:
226937.475 Da
References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]
General Function:
Voltage-gated sodium channel activity
Specific Function:
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient.
Gene Name:
SCN7A
Uniprot ID:
Q01118
Molecular Weight:
193491.605 Da
References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]
General Function:
Voltage-gated sodium channel activity
Specific Function:
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. In macrophages and melanoma cells, isoform 5 may participate in the control of podosome and invadopodia formation.
Gene Name:
SCN8A
Uniprot ID:
Q9UQD0
Molecular Weight:
225278.005 Da
References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]
General Function:
Voltage-gated sodium channel activity
Specific Function:
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-sensitive Na(+) channel isoform. Plays a role in pain mechanisms, especially in the development of inflammatory pain (By similarity).
Gene Name:
SCN9A
Uniprot ID:
Q15858
Molecular Weight:
226370.175 Da
References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]
General Function:
Voltage-gated sodium channel activity involved in purkinje myocyte action potential
Specific Function:
Crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. The subunit beta-1 can modulate multiple alpha subunit isoforms from brain, skeletal muscle, and heart. Its association with neurofascin may target the sodium channels to the nodes of Ranvier of developing axons and retain these channels at the nodes in mature myelinated axons.Isoform 2: Cell adhesion molecule that plays a critical role in neuronal migration and pathfinding during brain development. Stimulates neurite outgrowth.
Gene Name:
SCN1B
Uniprot ID:
Q07699
Molecular Weight:
24706.955 Da
References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]
General Function:
Voltage-gated sodium channel activity involved in cardiac muscle cell action potential
Specific Function:
Crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. The subunit beta-2 causes an increase in the plasma membrane surface area and in its folding into microvilli. Interacts with TNR may play a crucial role in clustering and regulation of activity of sodium channels at nodes of Ranvier (By similarity).
Gene Name:
SCN2B
Uniprot ID:
O60939
Molecular Weight:
24325.69 Da
References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]
General Function:
Voltage-gated sodium channel activity involved in cardiac muscle cell action potential
Specific Function:
Modulates channel gating kinetics. Causes unique persistent sodium currents. Inactivates the sodium channel opening more slowly than the subunit beta-1. Its association with neurofascin may target the sodium channels to the nodes of Ranvier of developing axons and retain these channels at the nodes in mature myelinated axons (By similarity).
Gene Name:
SCN3B
Uniprot ID:
Q9NY72
Molecular Weight:
24702.08 Da
References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]
General Function:
Voltage-gated sodium channel activity involved in cardiac muscle cell action potential
Specific Function:
Modulates channel gating kinetics. Causes negative shifts in the voltage dependence of activation of certain alpha sodium channels, but does not affect the voltage dependence of inactivation. Modulates the suceptibility of the sodium channel to inhibition by toxic peptides from spider, scorpion, wasp and sea anemone venom.
Gene Name:
SCN4B
Uniprot ID:
Q8IWT1
Molecular Weight:
24968.755 Da
References
  1. Wikipedia. Tetrodotoxin. Last Updated 25 July 2009. [Link]