You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on Toxin, Toxin Target Database.
Record Information
Version2.0
Creation Date2014-08-29 05:47:14 UTC
Update Date2014-12-24 20:26:40 UTC
Accession NumberT3D4153
Identification
Common NamePhenylacetic acid
ClassSmall Molecule
DescriptionPhenylacetic acid is a uremic toxin. Uremic toxins can be subdivided into three major groups based upon their chemical and physical characteristics: 1) small, water-soluble, non-protein-bound compounds, such as urea; 2) small, lipid-soluble and/or protein-bound compounds, such as the phenols and 3) larger so-called middle-molecules, such as beta2-microglobulin. Chronic exposure of uremic toxins can lead to a number of conditions including renal damage, chronic kidney disease and cardiovascular disease. Phenyl acetate (or phenylacetate) is a carboxylic acid ester that has been found in the biofluids of patients with nephritis and/or hepatitis as well as patients with phenylketonuria (PKU). Excess phenylalanine in the body can be disposed of through a transamination process leading to the production of phenylpyruvate. The phenylpyruvate can be further metabolized into a number of products. Decarboxylation of phenylpyruvate gives phenylacetate, while a reduction reaction gives phenyllactate. The phenylacetate can be further conjugated with glutamine to give phenylacetyl glutamine. All of these metabolites can be detected in serum and urine of PKU patients. Phenyl acetate is also produced endogenously as the metabolite of 2-Phenylethylamine, which is mainly metabolized by monoamine oxidase to form phenyl acetate. 2-phenylethylamine is an endogenous amphetamine which may modulate central adrenergic functions, and the urinary phenyl acetate levels have been postulated as a marker for depression. Phenylacetate is also found in essential oils, e.g. neroli, rose oil, free and as esters' and in many fruits. As a result it is used as a perfumery and flavoring ingredient. (1, 2, 3).
Compound Type
  • Food Toxin
  • Industrial/Workplace Toxin
  • Metabolite
  • Natural Compound
  • Organic Compound
  • Uremic Toxin
Chemical Structure
Thumb
Synonyms
Synonym
2-Phenylacetate
2-Phenylacetic acid
2-Phenylethanoate
2-Phenylethanoic acid
a-Toluate
a-Toluic acid
alpha-Toluate
alpha-Toluic acid
Benzeneacetate
Benzeneacetic acid
Benzylformate
Benzylformic acid
Omega-Phenylacetate
Omega-Phenylacetic acid
Phenylacetate
Phenylethanoate
Phenylethanoic acid
w-Phenylacetate
w-Phenylacetic acid
Chemical FormulaC8H8O2
Average Molecular Mass136.148 g/mol
Monoisotopic Mass136.052 g/mol
CAS Registry Number103-82-2
IUPAC Name2-phenylacetic acid
Traditional Nameω-phenylacetic acid
SMILESOC(=O)CC1=CC=CC=C1
InChI IdentifierInChI=1S/C8H8O2/c9-8(10)6-7-4-2-1-3-5-7/h1-5H,6H2,(H,9,10)
InChI KeyInChIKey=WLJVXDMOQOGPHL-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as benzene and substituted derivatives. These are aromatic compounds containing one monocyclic ring system consisting of benzene.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassNot Available
Direct ParentBenzene and substituted derivatives
Alternative Parents
Substituents
  • Monocyclic benzene moiety
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Organic oxygen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginEndogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point76.7°C
Boiling Point265.5°C
Solubility16.6 mg/mL
LogP1.41
Predicted Properties
PropertyValueSource
Water Solubility3.61 mg/mLALOGPS
logP1.72ALOGPS
logP1.61ChemAxon
logS-1.6ALOGPS
pKa (Strongest Acidic)4.55ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area37.3 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity37.37 m3·mol-1ChemAxon
Polarizability13.85 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
GC-MSGC-MS Spectrum - GC-MS (1 TMS)splash10-0006-9700000000-c07461cdad68959aa53fView in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MSsplash10-0006-9200000000-dc43e5e062b0ed500c5fView in MoNA
GC-MSGC-MS Spectrum - EI-Bsplash10-0006-9100000000-de65c7c0092343a4e599View in MoNA
GC-MSGC-MS Spectrum - GC-MSsplash10-0006-9700000000-c07461cdad68959aa53fView in MoNA
GC-MSGC-MS Spectrum - GC-EI-TOFsplash10-0006-9700000000-43e86e45beae2fa6704fView in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS)splash10-0006-9100000000-aaef76d181aebe492bbeView in MoNA
LC-MS/MSLC-MS/MS Spectrum - EI-B (HITACHI M-80B) , Positivesplash10-0006-9100000000-de65c7c0092343a4e599View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-IT , negativesplash10-0006-9000000000-6ca33b098558bf13801cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - , negativesplash10-000i-0900000000-f898aafe4cecc87d26f1View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00kr-2900000000-94a6f40f937bf9d7e4c7View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0006-9500000000-8d3540e40bfc0e4c0e5fView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0006-9000000000-417ad1f13a593ac780b9View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-000l-5900000000-0ed04a623daaf32fffdaView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-000l-8900000000-709928d6b823240d3528View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00kf-9600000000-4a7739132344f3dec710View in MoNA
MSMass Spectrum (Electron Ionization)splash10-0006-9100000000-1e23fd8e6ce900cd8e4cView in MoNA
1D NMR1H NMR SpectrumNot Available
1D NMR13C NMR SpectrumNot Available
1D NMR13C NMR SpectrumNot Available
1D NMR1H NMR SpectrumNot Available
1D NMR13C NMR SpectrumNot Available
2D NMR[1H,13C] 2D NMR SpectrumNot Available
Toxicity Profile
Route of ExposureEndogenous, Ingestion, Dermal (contact)
Mechanism of ToxicityUremic toxins such as phenylacetic acid are actively transported into the kidneys via organic ion transporters (especially OAT3). Increased levels of uremic toxins can stimulate the production of reactive oxygen species. This seems to be mediated by the direct binding or inhibition by uremic toxins of the enzyme NADPH oxidase (especially NOX4 which is abundant in the kidneys and heart) (5). Reactive oxygen species can induce several different DNA methyltransferases (DNMTs) which are involved in the silencing of a protein known as KLOTHO. KLOTHO has been identified as having important roles in anti-aging, mineral metabolism, and vitamin D metabolism. A number of studies have indicated that KLOTHO mRNA and protein levels are reduced during acute or chronic kidney diseases in response to high local levels of reactive oxygen species (6)
MetabolismUremic toxins tend to accumulate in the blood either through dietary excess or through poor filtration by the kidneys. Most uremic toxins are metabolic waste products and are normally excreted in the urine or feces.
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesNaturally produced by the body (endogenous).
Minimum Risk LevelNot Available
Health EffectsChronic exposure to uremic toxins can lead to a number of conditions including renal damage, chronic kidney disease and cardiovascular disease.
SymptomsAs a uremic toxin, this compound can cause uremic syndrome. Uremic syndrome may affect any part of the body and can cause nausea, vomiting, loss of appetite, and weight loss. It can also cause changes in mental status, such as confusion, reduced awareness, agitation, psychosis, seizures, and coma. Abnormal bleeding, such as bleeding spontaneously or profusely from a very minor injury can also occur. Heart problems, such as an irregular heartbeat, inflammation in the sac that surrounds the heart (pericarditis), and increased pressure on the heart can be seen in patients with uremic syndrome. Shortness of breath from fluid buildup in the space between the lungs and the chest wall (pleural effusion) can also be present.
TreatmentKidney dialysis is usually needed to relieve the symptoms of uremic syndrome until normal kidney function can be restored.
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDNot Available
HMDB IDHMDB00209
PubChem Compound ID999
ChEMBL IDCHEMBL1044
ChemSpider ID10181341
KEGG IDC07086
UniProt IDNot Available
OMIM ID
ChEBI ID30745
BioCyc IDPHENYLACETATE
CTD IDNot Available
Stitch IDNot Available
PDB IDPAC
ACToR IDNot Available
Wikipedia LinkPhenylacetic_acid
References
Synthesis ReferenceZhou, Shu-jing; Li, Jin-lian; Luan, Fang. New synthetic method for benzeneacetic acid. Huaxue Yu Shengwu Gongcheng (2005), 22(2), 43-44.
MSDSLink
General References
  1. Ostergaard J, Larsen C: Bioreversible derivatives of phenol. 2. Reactivity of carbonate esters with fatty acid-like structures towards hydrolysis in aqueous solutions. Molecules. 2007 Oct 30;12(10):2396-412. [17978765 ]
  2. Lorentz K, Flatter B, Augustin E: Arylesterase in serum: elaboration and clinical application of a fixed-incubation method. Clin Chem. 1979 Oct;25(10):1714-20. [476920 ]
  3. Sabelli HC, Fawcett J, Gusovsky F, Javaid J, Edwards J, Jeffriess H: Urinary phenyl acetate: a diagnostic test for depression? Science. 1983 Jun 10;220(4602):1187-8. [6857245 ]
  4. Duranton F, Cohen G, De Smet R, Rodriguez M, Jankowski J, Vanholder R, Argiles A: Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol. 2012 Jul;23(7):1258-70. doi: 10.1681/ASN.2011121175. Epub 2012 May 24. [22626821 ]
  5. Schulz AM, Terne C, Jankowski V, Cohen G, Schaefer M, Boehringer F, Tepel M, Kunkel D, Zidek W, Jankowski J: Modulation of NADPH oxidase activity by known uraemic retention solutes. Eur J Clin Invest. 2014 Aug;44(8):802-11. doi: 10.1111/eci.12297. [25041433 ]
  6. Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461. [22419041 ]
  7. Jankowski J, van der Giet M, Jankowski V, Schmidt S, Hemeier M, Mahn B, Giebing G, Tolle M, Luftmann H, Schluter H, Zidek W, Tepel M: Increased plasma phenylacetic acid in patients with end-stage renal failure inhibits iNOS expression. J Clin Invest. 2003 Jul;112(2):256-64. [12865413 ]
  8. Pontoni G, Rotondo F, Spagnuolo G, Aurino MT, Carteni-Farina M, Zappia V, Lama G: Diagnosis and follow-up of cystinuria: use of proton magnetic resonance spectroscopy. Amino Acids. 2000;19(2):469-76. [11128553 ]
  9. Rubin A, Knadler MP, Ho PP, Bechtol LD, Wolen RL: Stereoselective inversion of (R)-fenoprofen to (S)-fenoprofen in humans. J Pharm Sci. 1985 Jan;74(1):82-4. [3920382 ]
  10. Davis BA, Kennedy SH, D'Souza J, Durden DA, Goldbloom DS, Boulton AA: Correlations of plasma and urinary phenylacetic acid and phenylethylamine concentrations with eating behavior and mood rating scores in brofaromine-treated women with bulimia nervosa. J Psychiatry Neurosci. 1994 Jul;19(4):282-8. [7918350 ]
  11. Silvennoinen R, Malminiemi K, Malminiemi O, Seppala E, Vilpo J: Pharmacokinetics of chlorambucil in patients with chronic lymphocytic leukaemia: comparison of different days, cycles and doses. Pharmacol Toxicol. 2000 Nov;87(5):223-8. [11129502 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Glyceraldehyde oxidoreductase activity
Specific Function:
Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies.
Gene Name:
AKR1B1
Uniprot ID:
P15121
Molecular Weight:
35853.125 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5096 uMNot AvailableBindingDB 16419
References
  1. Ferrari AM, Degliesposti G, Sgobba M, Rastelli G: Validation of an automated procedure for the prediction of relative free energies of binding on a set of aldose reductase inhibitors. Bioorg Med Chem. 2007 Dec 15;15(24):7865-77. Epub 2007 Aug 22. [17870536 ]
  2. Schulz AM, Terne C, Jankowski V, Cohen G, Schaefer M, Boehringer F, Tepel M, Kunkel D, Zidek W, Jankowski J: Modulation of NADPH oxidase activity by known uraemic retention solutes. Eur J Clin Invest. 2014 Aug;44(8):802-11. doi: 10.1111/eci.12297. [25041433 ]
  3. Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461. [22419041 ]
General Function:
Sh2 domain binding
Specific Function:
Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosines residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP.
Gene Name:
LCK
Uniprot ID:
P06239
Molecular Weight:
58000.15 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Dissociation>50000 uMNot AvailableBindingDB 16419
References
  1. Hajduk PJ, Zhou MM, Fesik SW: NMR-based discovery of phosphotyrosine mimetics that bind to the Lck SH2 domain. Bioorg Med Chem Lett. 1999 Aug 16;9(16):2403-6. [10476877 ]
  2. Schulz AM, Terne C, Jankowski V, Cohen G, Schaefer M, Boehringer F, Tepel M, Kunkel D, Zidek W, Jankowski J: Modulation of NADPH oxidase activity by known uraemic retention solutes. Eur J Clin Invest. 2014 Aug;44(8):802-11. doi: 10.1111/eci.12297. [25041433 ]
  3. Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461. [22419041 ]
General Function:
Vitamin d binding
Specific Function:
May have weak glycosidase activity towards glucuronylated steroids. However, it lacks essential active site Glu residues at positions 239 and 872, suggesting it may be inactive as a glycosidase in vivo. May be involved in the regulation of calcium and phosphorus homeostasis by inhibiting the synthesis of active vitamin D (By similarity). Essential factor for the specific interaction between FGF23 and FGFR1 (By similarity).The Klotho peptide generated by cleavage of the membrane-bound isoform may be an anti-aging circulating hormone which would extend life span by inhibiting insulin/IGF1 signaling.
Gene Name:
KL
Uniprot ID:
Q9UEF7
Molecular Weight:
116179.815 Da
References
  1. Schulz AM, Terne C, Jankowski V, Cohen G, Schaefer M, Boehringer F, Tepel M, Kunkel D, Zidek W, Jankowski J: Modulation of NADPH oxidase activity by known uraemic retention solutes. Eur J Clin Invest. 2014 Aug;44(8):802-11. doi: 10.1111/eci.12297. [25041433 ]
  2. Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461. [22419041 ]
General Function:
Superoxide-generating nadph oxidase activity
Specific Function:
Constitutive NADPH oxidase which generates superoxide intracellularly upon formation of a complex with CYBA/p22phox. Regulates signaling cascades probably through phosphatases inhibition. May function as an oxygen sensor regulating the KCNK3/TASK-1 potassium channel and HIF1A activity. May regulate insulin signaling cascade. May play a role in apoptosis, bone resorption and lipolysaccharide-mediated activation of NFKB. May produce superoxide in the nucleus and play a role in regulating gene expression upon cell stimulation. Isoform 3 is not functional. Isoform 5 and isoform 6 display reduced activity.Isoform 4: Involved in redox signaling in vascular cells. Constitutively and NADPH-dependently generates reactive oxygen species (ROS). Modulates the nuclear activation of ERK1/2 and the ELK1 transcription factor, and is capable of inducing nuclear DNA damage. Displays an increased activity relative to isoform 1.
Gene Name:
NOX4
Uniprot ID:
Q9NPH5
Molecular Weight:
66930.995 Da
References
  1. Schulz AM, Terne C, Jankowski V, Cohen G, Schaefer M, Boehringer F, Tepel M, Kunkel D, Zidek W, Jankowski J: Modulation of NADPH oxidase activity by known uraemic retention solutes. Eur J Clin Invest. 2014 Aug;44(8):802-11. doi: 10.1111/eci.12297. [25041433 ]
  2. Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461. [22419041 ]
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenadine. Transports benzylpenicillin (PCG), estrone-3-sulfate (E1S), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), p-amino-hippurate (PAH), acyclovir (ACV) and ochratoxin (OTA).
Gene Name:
SLC22A8
Uniprot ID:
Q8TCC7
Molecular Weight:
59855.585 Da
References
  1. Schulz AM, Terne C, Jankowski V, Cohen G, Schaefer M, Boehringer F, Tepel M, Kunkel D, Zidek W, Jankowski J: Modulation of NADPH oxidase activity by known uraemic retention solutes. Eur J Clin Invest. 2014 Aug;44(8):802-11. doi: 10.1111/eci.12297. [25041433 ]
  2. Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461. [22419041 ]