Fumaric acid (T3D4237)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (17)XML
Targets (17)
Record Information
Version2.0
Creation Date2014-08-29 05:58:32 UTC
Update Date2014-12-24 20:26:43 UTC
Accession NumberT3D4237
Identification
Common NameFumaric acid
ClassSmall Molecule
DescriptionFumaric acid is a precursor to L-malate in the Krebs tricarboxylic acid cycle. It is formed by the oxidation of succinate by succinate dehydrogenase. Fumarate is converted by fumarase to malate. A fumarate is a salt or ester of the organic compound fumaric acid, a dicarboxylic acid. Fumarate has recently been recognized as an oncometabolite. (6). As a food additive, fumaric acid is used to impart a tart taste to processed foods. It is also used as an antifungal agent in boxed foods such as cake mixes and flours, as well as tortillas. Fumaric acid is also added to bread to increase the porosity of the final baked product. It is used to impart a sour taste to sourdough and rye bread. In cake mixes, it is used to maintain a low pH and prevent clumping of the flours used in the mix. In fruit drinks, fumaric acid is used to maintain a low pH which, in turn, helps to stabilize flavor and color. Fumaric acid also prevents the growth of E. coli in beverages when used in combination with sodium benzoate. When added to wines, fumaric acid helps to prevent further fermentation and yet maintain low pH and eliminate traces of metallic elements. In this fashion, it helps to stabilize the taste of wine. Fumaric acid can also be added to dairy products, sports drinks, jams, jellies and candies. Fumaric acid helps to break down bonds between gluten proteins in wheat and helps to create a more pliable dough. Fumaric acid is used in paper sizing, printer toner, and polyester resin for making molded walls.
Compound Type
  • Animal Toxin
  • Food Toxin
  • Lachrymator
  • Metabolite
  • Natural Compound
  • Organic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
(2E)-But-2-enedioate
(2E)-But-2-enedioic acid
(E)-2-Butenedioate
(E)-2-Butenedioic acid
2-(E)-Butenedioate
2-(E)-Butenedioic acid
Allomaleate
Allomaleic acid
Boletate
Boletic acid
FC 33
Fumarate
Lichenate
Lichenic acid
Sodium fumarate
trans-1,2-Ethylenedicarboxylate
trans-1,2-Ethylenedicarboxylic acid
trans-2-Butenedioate
trans-2-Butenedioic acid
trans-Butenedioate
trans-Butenedioic acid
Chemical FormulaC4H4O4
Average Molecular Mass116.072 g/mol
Monoisotopic Mass116.011 g/mol
CAS Registry Number110-17-8
IUPAC Name(2E)-but-2-enedioic acid
Traditional Namefumaric acid
SMILES[H]\C(=C(\[H])C(O)=O)C(O)=O
InChI IdentifierInChI=1S/C4H4O4/c5-3(6)1-2-4(7)8/h1-2H,(H,5,6)(H,7,8)/b2-1+
InChI KeyInChIKey=VZCYOOQTPOCHFL-OWOJBTEDSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as dicarboxylic acids and derivatives. These are organic compounds containing exactly two carboxylic acid groups.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassDicarboxylic acids and derivatives
Direct ParentDicarboxylic acids and derivatives
Alternative Parents
Substituents
  • Fatty acyl
  • Fatty acid
  • Unsaturated fatty acid
  • Dicarboxylic acid or derivatives
  • Carboxylic acid
  • Organic oxygen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginEndogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
  • Mitochondria
Biofluid LocationsNot Available
Tissue Locations
  • Prostate
Pathways
NameSMPDB LinkKEGG Link
Arginine and Proline MetabolismSMP00020 map00330
Aspartate MetabolismSMP00067 map00250
Citric Acid CycleSMP00057 map00020
Mitochondrial Electron Transport ChainSMP00355 map00190
Phenylalanine and Tyrosine MetabolismSMP00008 map00360
Tyrosine MetabolismSMP00006 map00350
Urea CycleSMP00059 Not Available
2-ketoglutarate dehydrogenase complex deficiencySMP00549 Not Available
Fumarase deficiencySMP00547 Not Available
Pyruvate Carboxylase DeficiencySMP00350 Not Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point549°C
Boiling PointNot Available
Solubility7.0 mg/mL
LogP0.46
Predicted Properties
PropertyValueSource
Water Solubility24.1 g/LALOGPS
logP0.21ALOGPS
logP-0.041ChemAxon
logS-0.68ALOGPS
pKa (Strongest Acidic)3.55ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area74.6 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity24.61 m³·mol⁻¹ChemAxon
Polarizability9.35 ųChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (2 TMS)splash10-0002-2940000000-e988056514d4ce4acc272014-06-16View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (2 TMS)splash10-0002-2960000000-a5ebaf2bbade922838ec2014-06-16View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (2 TMS)splash10-0002-2950000000-32afa4d45e0e72b174b42014-06-16View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (Non-derivatized)splash10-0002-0950000000-fe0f05c02c783d0b6f6b2014-06-16View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (2 TMS)splash10-006t-9530000000-0fc03f31f09dc8dbf4c62014-06-16View Spectrum
GC-MSGC-MS Spectrum - GC-MS (2 TMS)splash10-0002-3690000000-75089756992cdbe841e32014-06-16View Spectrum
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0002-9100000000-2cf649749b42cc0c610c2017-09-12View Spectrum
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0007-0890000000-b1c35cd55deb81254f662017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0002-2940000000-e988056514d4ce4acc272017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0002-2960000000-a5ebaf2bbade922838ec2017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0002-2950000000-32afa4d45e0e72b174b42017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0002-0950000000-fe0f05c02c783d0b6f6b2017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-006t-9530000000-0fc03f31f09dc8dbf4c62017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-0002-3690000000-75089756992cdbe841e32017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0002-0940000000-177fdb9168659029ffaa2017-09-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-01ba-9200000000-52f88e04bac0ff8cdf172016-09-22View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-00di-8920000000-06da44f348d0fe0358b32017-10-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_1) - 70eV, PositiveNot Available2021-11-05View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_1_1) - 70eV, PositiveNot Available2021-11-05View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_2_1) - 70eV, PositiveNot Available2021-11-05View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Negative (Annotated)splash10-00di-9100000000-57f13cd433a6fe4bf0b32012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Negative (Annotated)splash10-0229-9600000000-cd9e2979d0bb1e2a62f22012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Negative (Annotated)splash10-03k9-8900000000-dc50dbf8a50872383d542012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - EI-B (HITACHI RMU-6L) , Positivesplash10-0002-9100000000-b47e534bc82a6ed36e7c2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 10V, Negativesplash10-00di-9000000000-04b277f233e1bd56c9af2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 10V, Negativesplash10-03di-4900000000-99764eff7d7cb7bfaee32021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 35V, Negativesplash10-00di-9000000000-453b921a0aaf64cfd5582021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 40V, Positivesplash10-0f6x-9000000000-cd7e7026d13bb5fe844b2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 10V, Positivesplash10-00dj-9000000000-383c22a29e2769626c472021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 20V, Positivesplash10-0ir3-9000000000-3013847e2e0f9bf18d292021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 30V, Negativesplash10-00di-9000000000-9cc4f29b523ed34dc0b62021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 15V, Negativesplash10-00di-9000000000-d9885a6093f38dd8b9fa2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 45V, Negativesplash10-00di-9000000000-46fdee94b5a787f1b81f2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 35V, Negativesplash10-03k9-8900000000-3ff0fb725ec9dffc36882021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 20V, Negativesplash10-014m-9000000000-394fd8f1b59c7befec9d2021-09-20View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-014j-9800000000-dbf34563376daeb2901f2016-09-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00xs-9200000000-113bf08cdc77707ed3ad2016-09-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-00fr-9000000000-f32d7ec65e8649bc2b0a2016-09-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-014i-2900000000-408d53a9fff7acc8ca232016-09-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-014i-6900000000-f149e9e5a34e27dd4d4e2016-09-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0fxt-9000000000-cae5f71dc27daaf17d9e2016-09-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-00di-9000000000-3d34cd791255c022876a2021-09-21View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-00di-9000000000-55a5c43ec34fdd2cb0a42021-09-21View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0uk9-9000000000-7c9639a65d534cd8ff972021-09-21View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-000t-9000000000-c5eb63dc643f72e91ede2021-09-25View Spectrum
MSMass Spectrum (Electron Ionization)splash10-0092-9000000000-003dd2d9303272b2ebea2014-09-20View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, H2O, experimental)Not Available2012-12-04View Spectrum
1D NMR13C NMR Spectrum (1D, 125 MHz, H2O, experimental)Not Available2012-12-04View Spectrum
1D NMR1H NMR Spectrum (1D, 400 MHz, DMSO-d6, experimental)Not Available2014-09-20View Spectrum
1D NMR13C NMR Spectrum (1D, 22.53 MHz, DMSO-d6, experimental)Not Available2014-09-23View Spectrum
1D NMR1H NMR Spectrum (1D, D2O, experimental)Not Available2016-10-22View Spectrum
1D NMR13C NMR Spectrum (1D, D2O, experimental)Not Available2016-10-22View Spectrum
1D NMR1H NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
2D NMR[1H, 1H]-TOCSY. Unexported temporarily by An Chi on Oct 15, 2021 until json or nmrML file is generated. 2D NMR Spectrum (experimental)Not Available2012-12-04View Spectrum
2D NMR[1H, 13C]-HSQC NMR Spectrum (2D, 600 MHz, H2O, experimental)Not Available2012-12-04View Spectrum
Toxicity Profile
Route of ExposureEndogenous, ingestion, contact (skin and eyes)
Mechanism of ToxicityAcute Toxicity: Fumarate is also an endogenous electrophile and reacts spontaneously with cysteine residues in proteins by a Michael addition reaction to form S-(2-succinyl) cysteine, a process termed succination. Lachrymators such as fumarate are thought to act by attacking sulfhydryl functional groups in enzymes. One of the most probable protein targets is the TRPA1 ion channel that is expressed in sensory nerves (trigeminal nerve) of the eyes, nose, mouth and lungs. Chronic Toxicity: Fumarate is increasingly being identified as an oncometabolite. Fumarase or fumarate hydratase (FH) is a tumor suppressor, whose mutation is associated with the development of leiomyomata, renal cysts, and tumors. Loss of FH enzymatic activity results in accumulation of intracellular fumarate which has been proposed to act as a competitive inhibitor of 2-oxoglutarate-dependent oxygenases including the hypoxia-inducible factor (HIF) hydroxylases, thus activating oncogenic HIF pathways. Mitochondrial dysfunction is also associated with FH deficiency. Fumarate hydratase-deficient cells and tumors have been shown to accumulate fumarate to very high levels with multiple consequences including the activation of oncogenic pathways (6). Fumarate (and succinate) inhibit the activity or function of other members of the 2-oxoglutarate-dependent oxygenase superfamily, including histone demethylase enzymes (HDMs) and the TET family of 5-methlycytosine (5mC) hydroxylases which are critical in epigenetic regulation of gene expression.. Fumarate accumulation may also affect cytosolic pathways by inhibiting the reactions involved in the biosynthesis of arginine and purine. More recently it has been found that fumarate promotes p65 phosphorylation and p65 accumulation at the HIF-1α promoter through non-canonical signaling via the upstream Tank Binding Kinase 1 (TBK1). Fumarate is also an endogenous electrophile and reacts spontaneously with cysteine residues in proteins by a Michael addition reaction to form S-(2-succinyl) cysteine, a process termed succination. Accumulation of cellular fumarate has been shown to correlate directly with an increase in succinated proteins. Targets for succination include the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, adiponectin, cytoskeletal proteins, and endoplasmic reticulum chaperone proteins. Furthermore, evidence suggests that succination of these proteins in cells may impair their functions.
MetabolismFumarate is an intermediate in the citric acid cycle used by cells to produce energy in the form of adenosine triphosphate (ATP) from food. It is formed by the oxidation of succinate by the enzyme succinate dehydrogenase. Fumarate is then converted by the enzyme fumarase (fumarate hydratase) to malate.
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)Not listed by IARC. Has been implicated in oncogenesis (7, 8).
Uses/SourcesFumaric acid is naturally produced by the body, however for industrial applications it is synthesized chemically. Fumaric acid is used to impart a tart taste to processed foods. It is also used as an antifungal agent in boxed foods such as cake mixes and flours, as well as tortillas. Fumaric acid is also added to bread to increase the porosity of the final baked product. It is used to impart a sour taste to sourdough and rye bread. In cake mixes, it is used to maintain a low pH and prevent clumping of the flours used in the mix. In fruit drinks, fumaric acid is used to maintain a low pH which, in turn, helps to stabilize flavor and color. Fumaric acid also prevents the growth of E. coli in beverages when used in combination with sodium benzoate. When added to wines, fumaric acid helps to prevent further fermentation and yet maintain low pH and eliminate traces of metallic elements. In this fashion, it helps to stabilize the taste of wine. Fumaric acid can also be added to dairy products, sports drinks, jams, jellies and candies. Fumaric acid helps to break down bonds between gluten proteins in wheat and helps to create a more pliable dough. Fumaric acid is used in paper sizing, printer toner, and polyester resin for making molded walls.
Minimum Risk LevelNot Available
Health EffectsAcute exposure to fumaric acid can cause skin redness (skin contact), cough or sore throat (inhalation), abdominal cramps, nausea and diarrhea (ingestion). Chronically high levels of fumaric acid are associated with at least 3 inborn errors of metabolism including: 2-Ketoglutarate dehydrogenase complex deficiency, Fumarase deficiency and Pyruvate carboxylase deficiency. Fumarase deficiency causes encephalopathy, severe mental retardation, unusual facial features, brain malformation, and epileptic seizures. High intracellular fumaric acid levels are associated with the development of renal cancer, leiomyomata, renal cysts, and tumors.
SymptomsAcute exposure to fumaric acid can cause eye and skin irritation, cough or sore throat (inhalation), abdominal cramps, nausea and diarrhea (ingestion).
TreatmentAcute exposure: EYES: irrigate opened eyes for several minutes under running water. INGESTION: do not induce vomiting. Rinse mouth with water (never give anything by mouth to an unconscious person). Seek immediate medical advice. SKIN: should be treated immediately by rinsing the affected parts in cold running water for at least 15 minutes, followed by thorough washing with soap and water. If necessary, the person should shower and change contaminated clothing and shoes, and then must seek medical attention. Chronic Exposure: There is no treatment for fumarase deficiencies. Only palliative care is possible. For cancers caused by intracellular fumarate excess, there are a wide variety of cancer treatments including drugs and surgery.
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01677
HMDB IDHMDB00134
PubChem Compound ID444972
ChEMBL IDCHEMBL503160
ChemSpider ID10197150
KEGG IDC00122
UniProt IDNot Available
OMIM ID
ChEBI ID18012
BioCyc IDFUM
CTD IDNot Available
Stitch IDNot Available
PDB IDFUM
ACToR IDNot Available
Wikipedia LinkFumaric acid
References
Synthesis Reference

Chung Kun Shih, Craig W. Gleason, Edmund H. Braun, II, “Solventless process for producing dialkyl fumarate-vinyl acetate copolymers.” U.S. Patent US4772674, issued September, 1980.

MSDSLink
General References
  1. Guneral F, Bachmann C: Age-related reference values for urinary organic acids in a healthy Turkish pediatric population. Clin Chem. 1994 Jun;40(6):862-6. [8087979 ]
  2. Redjems-Bennani N, Jeandel C, Lefebvre E, Blain H, Vidailhet M, Gueant JL: Abnormal substrate levels that depend upon mitochondrial function in cerebrospinal fluid from Alzheimer patients. Gerontology. 1998;44(5):300-4. [9693263 ]
  3. Shoemaker JD, Elliott WH: Automated screening of urine samples for carbohydrates, organic and amino acids after treatment with urease. J Chromatogr. 1991 Jan 2;562(1-2):125-38. [2026685 ]
  4. Hoffmann GF, Meier-Augenstein W, Stockler S, Surtees R, Rating D, Nyhan WL: Physiology and pathophysiology of organic acids in cerebrospinal fluid. J Inherit Metab Dis. 1993;16(4):648-69. [8412012 ]
  5. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM: Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009 Feb 12;457(7231):910-4. doi: 10.1038/nature07762. [19212411 ]
  6. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
  7. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  8. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  9. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. Methylcytosine dioxygenase TET2
General Function:
Zinc ion binding
Specific Function:
Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation. Has a preference for 5-hydroxymethylcytosine in CpG motifs. Also mediates subsequent conversion of 5hmC into 5-formylcytosine (5fC), and conversion of 5fC to 5-carboxylcytosine (5caC). Conversion of 5mC into 5hmC, 5fC and 5caC probably constitutes the first step in cytosine demethylation. Methylation at the C5 position of cytosine bases is an epigenetic modification of the mammalian genome which plays an important role in transcriptional regulation. In addition to its role in DNA demethylation, also involved in the recruitment of the O-GlcNAc transferase OGT to CpG-rich transcription start sites of active genes, thereby promoting histone H2B GlcNAcylation by OGT.
Gene Name:
TET2
Uniprot ID:
Q6N021
Molecular Weight:
223809.995 Da
References
  1. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  2. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  3. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
Target Details
2. Egl nine homolog 2
General Function:
Peptidyl-proline 4-dioxygenase activity
Specific Function:
Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle. Also regulates susceptibility to normoxic oxidative neuronal death. Links oxygen sensing to cell cycle and primary cilia formation by hydroxylating the critical centrosome component CEP192 which promotes its ubiquitination and subsequent proteasomal degradation. Hydroxylates IKBKB, mediating NF-kappaB activation in hypoxic conditions. Target proteins are preferentially recognized via a LXXLAP motif.
Gene Name:
EGLN2
Uniprot ID:
Q96KS0
Molecular Weight:
43650.03 Da
References
  1. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  2. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  3. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
Target Details
3. Egl nine homolog 1
General Function:
Peptidyl-proline dioxygenase activity
Specific Function:
Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferentially recognized via a LXXLAP motif.
Gene Name:
EGLN1
Uniprot ID:
Q9GZT9
Molecular Weight:
46020.585 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50220 uMNot AvailableBindingDB 26122
Dissociation200 uMNot AvailableBindingDB 26122
References
  1. Leung IK, Demetriades M, Hardy AP, Lejeune C, Smart TJ, Szollossi A, Kawamura A, Schofield CJ, Claridge TD: Reporter ligand NMR screening method for 2-oxoglutarate oxygenase inhibitors. J Med Chem. 2013 Jan 24;56(2):547-55. doi: 10.1021/jm301583m. Epub 2013 Jan 4. [23234607 ]
  2. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  3. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  4. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
Target Details
4. Egl nine homolog 3
General Function:
Peptidyl-proline 4-dioxygenase activity
Specific Function:
Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis. Under normoxia, hydroxylates and regulates the stability of ADRB2. Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex. In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity. Also essential for hypoxic regulation of neutrophilic inflammation. Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway. Target proteins are preferentially recognized via a LXXLAP motif.
Gene Name:
EGLN3
Uniprot ID:
Q9H6Z9
Molecular Weight:
27261.06 Da
References
  1. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  2. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  3. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
Target Details
5. Histone lysine demethylase PHF8
General Function:
Zinc ion binding
Specific Function:
Histone lysine demethylase with selectivity for the di- and monomethyl states that plays a key role cell cycle progression, rDNA transcription and brain development. Demethylates mono- and dimethylated histone H3 'Lys-9' residue (H3K9Me1 and H3K9Me2), dimethylated H3 'Lys-27' (H3K27Me2) and monomethylated histone H4 'Lys-20' residue (H4K20Me1). Acts as a transcription activator as H3K9Me1, H3K9Me2, H3K27Me2 and H4K20Me1 are epigenetic repressive marks. Involved in cell cycle progression by being required to control G1-S transition. Acts as a coactivator of rDNA transcription, by activating polymerase I (pol I) mediated transcription of rRNA genes. Required for brain development, probably by regulating expression of neuron-specific genes. Only has activity toward H4K20Me1 when nucleosome is used as a substrate and when not histone octamer is used as substrate. May also have weak activity toward dimethylated H3 'Lys-36' (H3K36Me2), however, the relevance of this result remains unsure in vivo. Specifically binds trimethylated 'Lys-4' of histone H3 (H3K4me3), affecting histone demethylase specificity: has weak activity toward H3K9Me2 in absence of H3K4me3, while it has high activity toward H3K9me2 when binding H3K4me3.
Gene Name:
PHF8
Uniprot ID:
Q9UPP1
Molecular Weight:
117862.955 Da
References
  1. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  2. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  3. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
Target Details
6. Lysine-specific demethylase 4A
General Function:
Zinc ion binding
Specific Function:
Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate. Participates in transcriptional repression of ASCL2 and E2F-responsive promoters via the recruitment of histone deacetylases and NCOR1, respectively.Isoform 2: Crucial for muscle differentiation, promotes transcriptional activation of the Myog gene by directing the removal of repressive chromatin marks at its promoter. Lacks the N-terminal demethylase domain.
Gene Name:
KDM4A
Uniprot ID:
O75164
Molecular Weight:
120661.265 Da
References
  1. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  2. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  3. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
Target Details
7. Lysine-specific demethylase 4B
General Function:
Zinc ion binding
Specific Function:
Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27', H3 'Lys-36' nor H4 'Lys-20'. Only able to demethylate trimethylated H3 'Lys-9', with a weaker activity than KDM4A, KDM4C and KDM4D. Demethylation of Lys residue generates formaldehyde and succinate.
Gene Name:
KDM4B
Uniprot ID:
O94953
Molecular Weight:
121895.515 Da
References
  1. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  2. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  3. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
Target Details
8. Lysine-specific demethylase 4C
General Function:
Zinc ion binding
Specific Function:
Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate.
Gene Name:
KDM4C
Uniprot ID:
Q9H3R0
Molecular Weight:
119980.795 Da
References
  1. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  2. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  3. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
Target Details
9. Lysine-specific demethylase 4D
General Function:
Metal ion binding
Specific Function:
Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27', H3 'Lys-36' nor H4 'Lys-20'. Demethylates both di- and trimethylated H3 'Lys-9' residue, while it has no activity on monomethylated residues. Demethylation of Lys residue generates formaldehyde and succinate.
Gene Name:
KDM4D
Uniprot ID:
Q6B0I6
Molecular Weight:
58602.32 Da
References
  1. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  2. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  3. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
Target Details
10. Lysine-specific demethylase 5C
General Function:
Zinc ion binding
Specific Function:
Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. Participates in transcriptional repression of neuronal genes by recruiting histone deacetylases and REST at neuron-restrictive silencer elements. Represses the CLOCK-ARNTL/BMAL1 heterodimer-mediated transcriptional activation of the core clock component PER2 (By similarity).
Gene Name:
KDM5C
Uniprot ID:
P41229
Molecular Weight:
175718.565 Da
References
  1. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  2. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  3. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
Target Details
11. Lysine-specific demethylase PHF2
General Function:
Zinc ion binding
Specific Function:
Lysine demethylase that demethylates both histones and non-histone proteins. Enzymatically inactive by itself, and becomes active following phosphorylation by PKA: forms a complex with ARID5B and mediates demethylation of methylated ARID5B. Demethylation of ARID5B leads to target the PHF2-ARID5B complex to target promoters, where PHF2 mediates demethylation of dimethylated 'Lys-9' of histone H3 (H3K9me2), followed by transcription activation of target genes. The PHF2-ARID5B complex acts as a coactivator of HNF4A in liver. PHF2 is recruited to trimethylated 'Lys-4' of histone H3 (H3K4me3) at rDNA promoters and promotes expression of rDNA.
Gene Name:
PHF2
Uniprot ID:
O75151
Molecular Weight:
120773.925 Da
References
  1. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  2. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  3. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
Target Details
12. Methylcytosine dioxygenase TET1
General Function:
Zinc ion binding
Specific Function:
Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation. Also mediates subsequent conversion of 5hmC into 5-formylcytosine (5fC), and conversion of 5fC to 5-carboxylcytosine (5caC). Conversion of 5mC into 5hmC, 5fC and 5caC probably constitutes the first step in cytosine demethylation. Methylation at the C5 position of cytosine bases is an epigenetic modification of the mammalian genome which plays an important role in transcriptional regulation. In addition to its role in DNA demethylation, plays a more general role in chromatin regulation. Preferentially binds to CpG-rich sequences at promoters of both transcriptionally active and Polycomb-repressed genes. Involved in the recruitment of the O-GlcNAc transferase OGT to CpG-rich transcription start sites of active genes, thereby promoting histone H2B GlcNAcylation by OGT. Also involved in transcription repression of a subset of genes through recruitment of transcriptional repressors to promoters. Involved in the balance between pluripotency and lineage commitment of cells it plays a role in embryonic stem cells maintenance and inner cell mass cell specification.
Gene Name:
TET1
Uniprot ID:
Q8NFU7
Molecular Weight:
235306.965 Da
References
  1. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  2. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  3. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
Target Details
13. Serine/threonine-protein kinase TBK1
General Function:
Protein serine/threonine kinase activity
Specific Function:
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes. Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy. Phosphorylates and activates AKT1. Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C. Phosphorylates Borna disease virus (BDV) P protein.
Gene Name:
TBK1
Uniprot ID:
Q9UHD2
Molecular Weight:
83641.51 Da
References
  1. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  2. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  3. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
Target Details
14. Transmembrane prolyl 4-hydroxylase
General Function:
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, 2-oxoglutarate as one donor, and incorporation of one atom each of oxygen into both donors
Specific Function:
Catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates HIF1A at 'Pro-402' and 'Pro-564'. May function as a cellular oxygen sensor and, under normoxic conditions, may target HIF through the hydroxylation for proteasomal degradation via the von Hippel-Lindau ubiquitination complex.
Gene Name:
P4HTM
Uniprot ID:
Q9NXG6
Molecular Weight:
56660.535 Da
References
  1. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013 Sep 3;123(9):3652-8. doi: 10.1172/JCI67228. Epub 2013 Sep 3. [23999438 ]
  2. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling. J Biol Chem. 2014 Aug 29;289(35):24691-9. doi: 10.1074/jbc.M114.568162. Epub 2014 Jul 15. [25028521 ]
  3. Yang M, Soga T, Pollard PJ, Adam J: The emerging role of fumarate as an oncometabolite. Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. [22866264 ]
Target Details
15. Alpha-ketoglutarate-dependent dioxygenase FTO
General Function:
Oxidative rna demethylase activity
Specific Function:
Dioxygenase that repairs alkylated DNA and RNA by oxidative demethylation. Has highest activity towards single-stranded RNA containing 3-methyluracil, followed by single-stranded DNA containing 3-methylthymine. Has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine (PubMed:18775698, PubMed:20376003). Specifically demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes (PubMed:22002720, PubMed:26458103). Has no activity towards 1-methylguanine. Has no detectable activity towards double-stranded DNA. Requires molecular oxygen, alpha-ketoglutarate and iron. Contributes to the regulation of the global metabolic rate, energy expenditure and energy homeostasis. Contributes to the regulation of body size and body fat accumulation (PubMed:18775698, PubMed:20376003).
Gene Name:
FTO
Uniprot ID:
Q9C0B1
Molecular Weight:
58281.53 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50150 uMNot AvailableBindingDB 26122
References
  1. Aik W, Demetriades M, Hamdan MK, Bagg EA, Yeoh KK, Lejeune C, Zhang Z, McDonough MA, Schofield CJ: Structural basis for inhibition of the fat mass and obesity associated protein (FTO). J Med Chem. 2013 May 9;56(9):3680-8. doi: 10.1021/jm400193d. Epub 2013 Apr 23. [23547775 ]
Target Details
16. Lysine-specific demethylase 4E
General Function:
Metal ion binding
Specific Function:
Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code.
Gene Name:
KDM4E
Uniprot ID:
B2RXH2
Molecular Weight:
56803.925 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC501600 uMNot AvailableBindingDB 26122
References
  1. Rose NR, Ng SS, Mecinovic J, Lienard BM, Bello SH, Sun Z, McDonough MA, Oppermann U, Schofield CJ: Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases. J Med Chem. 2008 Nov 27;51(22):7053-6. doi: 10.1021/jm800936s. [18942826 ]
Target Details
17. Transient receptor potential cation channel subfamily A member 1
General Function:
Temperature-gated cation channel activity
Specific Function:
Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function (PubMed:25389312, PubMed:25855297). Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, such as mustard oil, cinnamaldehyde, garlic and acrolein, an irritant from tears gas and vehicule exhaust fumes (PubMed:25389312, PubMed:20547126). Is also activated by menthol (in vitro)(PubMed:25389312). Acts also as a ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana (PubMed:25389312). May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system (By similarity).
Gene Name:
TRPA1
Uniprot ID:
O75762
Molecular Weight:
127499.88 Da
References
  1. Nilius B, Prenen J, Owsianik G: Irritating channels: the case of TRPA1. J Physiol. 2011 Apr 1;589(Pt 7):1543-9. doi: 10.1113/jphysiol.2010.200717. Epub 2010 Nov 15. [21078588 ]