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Record Information
Version2.0
Creation Date2009-11-17 20:50:33 UTC
Update Date2014-12-24 20:26:13 UTC
Accession NumberT3D3616
Identification
Common NameNodularin-R
ClassSmall Molecule
DescriptionNodularin-R is a cyclic nonribosomal peptide produced by the planktonic cyanobacterium Nodularia spumigena. This cyanobacterium forms blooms in brackish water bodies throughout the world. Nodularin-R is a pentapeptide and contains several unusual non-proteinogenic amino acids such as methyldehydrobutyrine and the _-amino acid ADDA, (all-S,all-E)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid. Nodularin-R is a cyanotoxin and poses a health risk for wild and domestic animals as well as humans. Nodularin-R is a potent hepatotoxin and may cause serious damage to the liver.
Compound Type
  • Amide
  • Amine
  • Bacterial Toxin
  • Ester
  • Ether
  • Microcystin
  • Natural Compound
  • Organic Compound
Chemical Structure
Thumb
Synonyms
Synonym
Cyclo((Z)-2,3-didehydro-N-methyl-2-aminobutanoyl-erythro-3-methyl-D-beta-aspartyl-L-arginyl-(2S,3S,4E,6E,8S,9S)-4,5,6,7-tetradehydro-9-methoxy-2,6,8-trimethyl-10-phenyl-3-aminodecanoyl-D-gamma-glutamyl)
Cyclo(L-arginyl-(2S,3S,4E,6E,8S,9S)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-4,6-decadienoyl-D-gamma-glutamyl-(2Z)-2-(methylamino)-2-butenoyl-(3S)-3-methyl-D-beta-aspartyl)
Nodularin
Chemical FormulaC41H60N8O10
Average Molecular Mass824.963 g/mol
Monoisotopic Mass824.443 g/mol
CAS Registry Number118399-22-7
IUPAC Name9-{3-[(diaminomethylidene)amino]propyl}-2-ethylidene-12-(6-methoxy-3,5-dimethyl-7-phenylhepta-1,3-dien-1-yl)-1,6,13-trimethyl-3,7,10,14,19-pentaoxo-1,4,8,11,15-pentaazacyclononadecane-5,16-dicarboxylic acid
Traditional Name9-{3-[(diaminomethylidene)amino]propyl}-2-ethylidene-12-(6-methoxy-3,5-dimethyl-7-phenylhepta-1,3-dien-1-yl)-1,6,13-trimethyl-3,7,10,14,19-pentaoxo-1,4,8,11,15-pentaazacyclononadecane-5,16-dicarboxylic acid
SMILESCOC(CC1=CC=CC=C1)C(C)C=C(C)C=CC1NC(=O)C(CCCN=C(N)N)NC(=O)C(C)C(NC(=O)C(=CC)N(C)C(=O)CCC(NC(=O)C1C)C(O)=O)C(O)=O
InChI IdentifierInChI=1S/C41H60N8O10/c1-8-31-38(54)48-34(40(57)58)26(5)36(52)46-29(15-12-20-44-41(42)43)37(53)45-28(25(4)35(51)47-30(39(55)56)18-19-33(50)49(31)6)17-16-23(2)21-24(3)32(59-7)22-27-13-10-9-11-14-27/h8-11,13-14,16-17,21,24-26,28-30,32,34H,12,15,18-20,22H2,1-7H3,(H,45,53)(H,46,52)(H,47,51)(H,48,54)(H,55,56)(H,57,58)(H4,42,43,44)/b17-16+,23-21+,31-8+
InChI KeyInChIKey=IXBQSRWSVIBXNC-ANPQUZCZSA-N
Chemical Taxonomy
DescriptionThis compound belongs to the class of chemical entities known as oligopeptides. These are organic compounds containing a sequence of between three and ten alpha-amino acids joined by peptide bonds.
KingdomChemical entities
Super ClassOrganic compounds
ClassOrganic acids and derivatives
Sub ClassCarboxylic acids and derivatives
Direct ParentOligopeptides
Alternative Parents
Substituents
  • Alpha-oligopeptide
  • Gamma-glutamyl alpha peptide
  • Macrolactam
  • Beta amino acid or derivatives
  • Alpha-amino acid or derivatives
  • Monocyclic benzene moiety
  • Dicarboxylic acid or derivatives
  • Benzenoid
  • Tertiary carboxylic acid amide
  • Carboxamide group
  • Guanidine
  • Lactam
  • Secondary carboxylic acid amide
  • Carboxylic acid
  • Dialkyl ether
  • Ether
  • Azacycle
  • Organoheterocyclic compound
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Carboximidamide
  • Hydrocarbon derivative
  • Organic oxygen compound
  • Organopnictogen compound
  • Carbonyl group
  • Organic oxide
  • Organic nitrogen compound
  • Organonitrogen compound
  • Organooxygen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External DescriptorsNot Available
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
Biofluid LocationsNot Available
Tissue Locations
  • Liver
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 Solubility0.00705 mg/mLALOGPS
logP1.58ALOGPS
logP-1.2ChemAxon
logS-5.1ALOGPS
pKa (Strongest Acidic)3.1ChemAxon
pKa (Strongest Basic)10.85ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count13ChemAxon
Hydrogen Donor Count8ChemAxon
Polar Surface Area284.94 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity220.69 m3·mol-1ChemAxon
Polarizability88.06 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
Toxicity Profile
Route of ExposureOral
Mechanism of ToxicityThe site of action of microcystins is the hepatocyte, the commonest cell type in the liver. They act by disrupting the cytoskeleton, the adaptable protein framework that constantly shapes and reshapes the cell as it responds to the environment. The cells die and this destroys the finer blood vessels of the liver leading to massive hepatic bleeding. The molecular target are a group of enzymes called protein phosphatases that play a role in regulating protein interactions and activities. Very well-defined types of protein phosphatase (type 1 and type 2A) are inhibited very specifically by very low concentrations of microcystins. This enzyme removes phosphate from a protein, a common step in many biochemical pathways. This inhibition, with subsequent build up of phosphorylated proteins, is believed to be a mechanism by which microcystins destroy livers. Microcystins also activate the enzyme phosphorylase b, which plays a very important role in the affairs of the hepatocyte. The combination of inhibition and activation is rapidly lethal to the cell. The specificity of some of these toxins makes them valuable research tools.
MetabolismMicrocystins are extremely stable and resist common chemical breakdown such as hydrolysis or oxidation under conditions found in most natural water bodies. These toxins can break down slowly at high temperature (40 °C or 104 o F ) at either very low (<1) or high (>9) pH. The half-life, the time it takes for one-half of the toxin to degrade, at pH 1 and 40 oC is 3 weeks; at typical ambient conditions half-life is 10 weeks.
Toxicity ValuesLD50 for rats and mice are in the range 36-122 micrograms/kg with the inhalation toxicity 180 mg/min/m3 or 43 micrograms/kg.
Lethal DoseIn comparing the available indications of hazards from cyanotoxins with other water-related health hazards, it is conspicuous that cyanotoxins have caused numerous fatal poisonings of livestock and wildlife, but no human fatalities due to oral uptake hav
Carcinogenicity (IARC Classification)3, not classifiable as to its carcinogenicity to humans. (3)
Uses/SourcesMicrocystins are produced by the cyanobacterial cells. When the algae dies, the cell walls burst, releasing the toxin into the water.
Minimum Risk LevelWHO developed a drinking water concentration limit of 1.5 μg/L for microcystin LR. They assumed that a 60 kg (132 lbs.) person drinks two liters of water each day and that 80% of the two liters is from a contaminated source.
Health EffectsLiver damage. While microcystin-LR does not cause cancer, microcystin may stimulate the growth of cancer cells.
SymptomsThe most common sign of human poisoning with microcystins is liver damage.
TreatmentMicrocystins can be broken down by some bacterial proteases.
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDNot Available
HMDB IDNot Available
PubChem Compound ID6437077
ChEMBL IDNot Available
ChemSpider ID4941665
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 LinkMicrocystin
References
Synthesis ReferenceNot Available
MSDSNot Available
General References
  1. Guinea J, Sanchez-Somolinos M, Cuevas O, Pelaez T, Bouza E: Fluconazole resistance mechanisms in Candida krusei: the contribution of efflux-pumps. Med Mycol. 2006 Sep;44(6):575-8. [16966178 ]
  2. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
  3. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated GenesNot Available

Targets

General Function:
Pyridoxal phosphate binding
Specific Function:
Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties.
Gene Name:
Not Available
Uniprot ID:
Q59GM9
Molecular Weight:
98828.62 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Pyridoxal phosphate binding
Specific Function:
Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties.
Gene Name:
Not Available
Uniprot ID:
Q59GM9
Molecular Weight:
98828.62 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein serine/threonine phosphatase inhibitor activity
Specific Function:
Inhibitor of protein phosphatase 1.
Gene Name:
PPP1R11
Uniprot ID:
O60927
Molecular Weight:
13952.425 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Signal transducer activity
Specific Function:
Key regulator of protein phosphatase 1C (PPP1C). Mediates binding to myosin. As part of the PPP1C complex, involved in dephosphorylation of PLK1. Capable of inhibiting HIF1AN-dependent suppression of HIF1A activity.
Gene Name:
PPP1R12A
Uniprot ID:
O14974
Molecular Weight:
115279.605 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Phosphatase regulator activity
Specific Function:
Regulates myosin phosphatase activity. Augments Ca(2+) sensitivity of the contractile apparatus.
Gene Name:
PPP1R12B
Uniprot ID:
O60237
Molecular Weight:
110402.735 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Not Available
Specific Function:
Regulates myosin phosphatase activity.
Gene Name:
PPP1R12C
Uniprot ID:
Q9BZL4
Molecular Weight:
84880.195 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein phosphatase inhibitor activity
Specific Function:
Inhibitor of PPP1CA. Has over 1000-fold higher inhibitory activity when phosphorylated, creating a molecular switch for regulating the phosphorylation status of PPP1CA substrates and smooth muscle contraction.
Gene Name:
PPP1R14A
Uniprot ID:
Q96A00
Molecular Weight:
16692.84 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein phosphatase inhibitor activity
Specific Function:
Inhibitor of PPP1CA. Has over 50-fold higher inhibitory activity when phosphorylated (By similarity).
Gene Name:
PPP1R14B
Uniprot ID:
Q96C90
Molecular Weight:
15910.78 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein serine/threonine phosphatase inhibitor activity
Specific Function:
Inhibitor of the PP1 regulatory subunit PPP1CA.
Gene Name:
PPP1R14C
Uniprot ID:
Q8TAE6
Molecular Weight:
17842.68 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein phosphatase inhibitor activity
Specific Function:
Inhibitor of PPP1CA. Has inhibitory activity only when phosphorylated, creating a molecular switch for regulating the phosphorylation status of PPP1CA substrates and smooth muscle contraction.
Gene Name:
PPP1R14D
Uniprot ID:
Q9NXH3
Molecular Weight:
16507.34 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein phosphatase type 1 regulator activity
Specific Function:
Recruits the serine/threonine-protein phosphatase PP1 to dephosphorylate the translation initiation factor eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis initiated by stress-inducible kinases and facilitating recovery of cells from stress. Down-regulates the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1 by PP1. May promote apoptosis by inducing TP53 phosphorylation on 'Ser-15'.
Gene Name:
PPP1R15A
Uniprot ID:
O75807
Molecular Weight:
73477.025 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein serine/threonine phosphatase activity
Specific Function:
Maintains low levels of EIF2S1 phosphorylation in unstressed cells by promoting its dephosphorylation by PP1.
Gene Name:
PPP1R15B
Uniprot ID:
Q5SWA1
Molecular Weight:
79150.69 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein phosphatase type 1 regulator activity
Specific Function:
Inhibits protein phosphatase 1 activity toward phosphorylase, myosin light chain and myosin substrates.
Gene Name:
PPP1R16A
Uniprot ID:
Q96I34
Molecular Weight:
57810.795 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein serine/threonine phosphatase inhibitor activity
Specific Function:
Inhibitor of protein-phosphatase 1. This protein may be important in hormonal control of glycogen metabolism. Hormones that elevate intracellular cAMP increase I-1 activity in many tissues. I-1 activation may impose cAMP control over proteins that are not directly phosphorylated by PKA. Following a rise in intracellular calcium, I-1 is inactivated by calcineurin (or PP2B). Does not inhibit type-2 phosphatases.
Gene Name:
PPP1R1A
Uniprot ID:
Q13522
Molecular Weight:
19011.15 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein serine/threonine phosphatase inhibitor activity
Specific Function:
Inhibitor of protein-phosphatase 1.
Gene Name:
PPP1R1B
Uniprot ID:
Q9UD71
Molecular Weight:
22962.575 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein serine/threonine phosphatase inhibitor activity
Specific Function:
Inhibitor of protein-phosphatase 1. Promotes cell growth and cell cycle progress at the G1/S transition. May increase cell susceptibility to TNF-induced apoptosis.
Gene Name:
PPP1R1C
Uniprot ID:
Q8WVI7
Molecular Weight:
12345.66 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Not Available
Specific Function:
Seems to act as a glycogen-targeting subunit for PP1. PP1 is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Plays an important role in glycogen synthesis but is not essential for insulin activation of glycogen synthase (By similarity).
Gene Name:
PPP1R3A
Uniprot ID:
Q16821
Molecular Weight:
125765.695 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein phosphatase regulator activity
Specific Function:
Acts as a glycogen-targeting subunit for phosphatase PP1. Facilitates interaction of the PP1 with enzymes of the glycogen metabolism and regulates its activity. Suppresses the rate at which PP1 dephosphorylates (inactivates) glycogen phosphorylase and enhances the rate at which it activates glycogen synthase and therefore limits glycogen breakdown. Its activity is inhibited by PYGL, resulting in inhibition of the glycogen synthase and glycogen phosphorylase phosphatase activities of PP1. Dramatically increases basal and insulin-stimulated glycogen synthesis upon overexpression in hepatocytes (By similarity).
Gene Name:
PPP1R3B
Uniprot ID:
Q86XI6
Molecular Weight:
32694.86 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein serine/threonine phosphatase activity
Specific Function:
Acts as a glycogen-targeting subunit for PP1 and regulates its activity. Activates glycogen synthase, reduces glycogen phosphorylase activity and limits glycogen breakdown. Dramatically increases basal and insulin-stimulated glycogen synthesis upon overexpression in a variety of cell types.
Gene Name:
PPP1R3C
Uniprot ID:
Q9UQK1
Molecular Weight:
36445.21 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein serine/threonine phosphatase activity
Specific Function:
Seems to act as a glycogen-targeting subunit for PP1. PP1 is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis.
Gene Name:
PPP1R3D
Uniprot ID:
O95685
Molecular Weight:
32558.72 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Phosphoprotein phosphatase activity
Specific Function:
Acts as a glycogen-targeting subunit for PP1. PP1 is involved in glycogen metabolism and contributes to the activation of glycogen synthase leading to an increase in glycogen synthesis.
Gene Name:
PPP1R3E
Uniprot ID:
Q9H7J1
Molecular Weight:
30643.2 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein phosphatase binding
Specific Function:
Glycogen-targeting subunit for protein phosphatase 1 (PP1).
Gene Name:
PPP1R3F
Uniprot ID:
Q6ZSY5
Molecular Weight:
82796.81 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.
General Function:
Protein phosphatase type 1 regulator activity
Specific Function:
Regulatory subunit of protein phosphatase 1.
Gene Name:
PPP1R7
Uniprot ID:
Q15435
Molecular Weight:
41563.805 Da
References
  1. Ecotoxicology Program Integrated Risk Assessment Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency. March 2009. Microcystins - A Brief Overview of their toxicity and effects, with special reference to fish, wildlife, and livestock.