T3DB: 4-Hydroxynonenal

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Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (16)XML

Targets (16)

Record Information

Version

2.0

Creation Date

2014-08-29 05:50:23 UTC

Update Date

2014-12-24 20:26:41 UTC

Accession Number

T3D4180

Identification

Common Name

4-Hydroxynonenal

Class

Small Molecule

Description

4-Hydroxynonenal 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. 4-Hydroxynonenal (HNE), one of the major end products of lipid peroxidation, has been shown to be involved in signal transduction and available evidence suggests that it can affect cell cycle events in a concentration-dependent manner. glutathione S-transferases (GSTs) can modulate the intracellular concentrations of HNE by affecting its generation during lipid peroxidation by reducing hydroperoxides and also by converting it into a glutathione conjugate. Overexpression of the Alpha class GSTs in cells leads to lower steady-state levels of HNE, and these cells acquire resistance to apoptosis induced by lipid peroxidation-causing agents such as H(2)O(2), UVA, superoxide anion, and pro-oxidant xenobiotics, suggesting that signaling for apoptosis by these agents is transduced through HNE. Cells with the capacity to exclude HNE from the intracellular environment at a faster rate are relatively more resistant to apoptosis caused by H(2)O(2), UVA, superoxide anion, and pro-oxidant xenobiotics as well as by HNE, suggesting that HNE may be a common denominator in mechanisms of apoptosis caused by oxidative stress. Transfection of adherent cells with HNE-metabolizing GSTs leads to transformation of these cells due to depletion of HNE. (1).

Compound Type

Ester
Food Toxin
Metabolite
Natural Compound
Organic Compound
Uremic Toxin

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
4-Hydroxy-2,3-nonenal
4-Hydroxy-2-Nonenal
4-Hydroxynon-2-enal
trans-4-Hydroxy-2-nonenal

Chemical Formula

C₉H₁₆O₂

Average Molecular Mass

156.222 g/mol

Monoisotopic Mass

156.115 g/mol

CAS Registry Number

75899-68-2

IUPAC Name

(2E)-4-hydroxynon-2-enal

Traditional Name

trans-4-hydroxy-2-nonenal

SMILES

[H]\C(C=O)=C(\[H])C(O)CCCCC

InChI Identifier

InChI=1/C9H16O2/c1-2-3-4-6-9(11)7-5-8-10/h5,7-9,11H,2-4,6H2,1H3/b7-5+

InChI Key

InChIKey=JVJFIQYAHPMBBX-FNORWQNLNA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as fatty alcohols. These are aliphatic alcohols consisting of a chain of a least six carbon atoms.

Kingdom

Organic compounds

Super Class

Lipids and lipid-like molecules

Class

Fatty Acyls

Sub Class

Fatty alcohols

Direct Parent

Fatty alcohols

Alternative Parents

Substituents

Fatty alcohol
Medium-chain aldehyde
Enal
Alpha,beta-unsaturated aldehyde
Secondary alcohol
Organic oxygen compound
Organic oxide
Hydrocarbon derivative
Organooxygen compound
Carbonyl group
Aldehyde
Alcohol
Aliphatic acyclic compound

Molecular Framework

Aliphatic acyclic compounds

External Descriptors

4-hydroxynon-2-enal (CHEBI:58968 )
Fatty aldehydes (LMFA06000051 )

Biological Properties

Status

Detected and Not Quantified

Origin

Endogenous

Cellular Locations

Cytoplasm
Extracellular
Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Not Available

Biological Roles

Not Available

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	Not Available
Boiling Point	Not Available
Solubility	Not Available
LogP	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	3.08 g/L	ALOGPS
logP	1.87	ALOGPS
logP	1.75	ChemAxon
logS	-1.7	ALOGPS
pKa (Strongest Acidic)	14.86	ChemAxon
pKa (Strongest Basic)	-2.9	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	37.3 Å²	ChemAxon
Rotatable Bond Count	6	ChemAxon
Refractivity	46.56 m³·mol⁻¹	ChemAxon
Polarizability	18.71 Å³	ChemAxon
Number of Rings	0	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0a4r-9000000000-2b2e86f0d26bfcdbaa7c	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positive	splash10-0a4i-9800000000-f25e4e5c5bfdea54d97c	2017-10-06	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-052r-1900000000-9e0485f40ddea525bfb2	2016-08-02	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0abi-9700000000-14b48d43b52506ea875a	2016-08-02	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0a4l-9000000000-c60e1ce771da41f3cef1	2016-08-02	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0a4i-1900000000-963698def33862d38ed8	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0a4i-3900000000-39790f81d0ebc18f6f71	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0006-9100000000-a4ef5b05613d7c911528	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-03di-0900000000-c09fa78f1a3efa8c0e31	2021-09-21	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0ab9-5900000000-5f46d902d1ecb2e14a93	2021-09-21	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0aor-9100000000-e66e02441083fb8392a5	2021-09-21	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0007-9300000000-9c3d48d2b69a51fb7d63	2021-09-25	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-00r6-9000000000-fdc847c35b84e0c9d894	2021-09-25	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0006-9000000000-d7140511cfc2bca207a8	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 100 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 100 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 1000 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 1000 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 200 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 200 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 300 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 300 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 400 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 500 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 500 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 600 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 600 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 700 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 700 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 800 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 800 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 900 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 900 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum

Toxicity Profile

Route of Exposure

Endogenous, Ingestion, Dermal (contact)

Mechanism of Toxicity

Uremic toxins such as 4-Hydroxynonenal 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) (3). 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 (4).

Metabolism

Uremic 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 Values

Not Available

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

Naturally produced by the body (endogenous).

Minimum Risk Level

Not Available

Health Effects

Chronic exposure to uremic toxins can lead to a number of conditions including renal damage, chronic kidney disease and cardiovascular disease.

Symptoms

As 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.

Treatment

Kidney 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

External Links

DrugBank ID

Not Available

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

Not Available

UniProt ID

Not Available

OMIM ID

ChEBI ID

58968

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Not Available

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

4-Hydroxynonenal

References

Synthesis Reference

Esterbauer, Hermann; Benedetti, Angelo; Lang, Johanna; Fulceri, Rosella; Fauler, Gunther; Comporti, Mario. Studies on the mechanism of formation of 4-hydroxynonenal during microsomal lipid peroxidation. Biochimica et Biophysica Acta, Lipids and Lipid Metabolism (1986), 876(1), 154-66.

MSDS

T3D4180.pdf

General References

Awasthi YC, Yang Y, Tiwari NK, Patrick B, Sharma A, Li J, Awasthi S: Regulation of 4-hydroxynonenal-mediated signaling by glutathione S-transferases. Free Radic Biol Med. 2004 Sep 1;37(5):607-19. [15288119 ]
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 ]
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 ]
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 ]
Selley ML, Close DR, Stern SE: The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer's disease. Neurobiol Aging. 2002 May-Jun;23(3):383-8. [11959400 ]
Selley ML: (E)-4-hydroxy-2-nonenal may be involved in the pathogenesis of Parkinson's disease. Free Radic Biol Med. 1998 Jul 15;25(2):169-74. [9667492 ]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. ATP synthase subunit alpha, mitochondrial

General Function:: Transmembrane transporter activity
Specific Function:: Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Subunits alpha and beta form the catalytic core in F(1). Rotation of the central stalk against the surrounding alpha(3)beta(3) subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits. Subunit alpha does not bear the catalytic high-affinity ATP-binding sites (By similarity).
Gene Name:: ATP5A1
Uniprot ID:: P25705
Molecular Weight:: 59750.06 Da

References

Reed TT, Pierce WM, Markesbery WR, Butterfield DA: Proteomic identification of HNE-bound proteins in early Alzheimer disease: Insights into the role of lipid peroxidation in the progression of AD. Brain Res. 2009 Jun 5;1274:66-76. doi: 10.1016/j.brainres.2009.04.009. Epub 2009 Apr 15. [19374891 ]
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 ]
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 ]

Target Details

2. Aldehyde dehydrogenase family 3 member B1

General Function:: Aldehyde dehydrogenase [nad(p)+] activity
Specific Function:: Oxidizes medium and long chain saturated and unsaturated aldehydes. Metabolizes also benzaldehyde. Low activity towards acetaldehyde and 3,4-dihydroxyphenylacetaldehyde. May not metabolize short chain aldehydes. May use both NADP(+) and NAD(+) as cofactors. May have a protective role against the cytotoxicity induced by lipid peroxidation.
Gene Name:: ALDH3B1
Uniprot ID:: P43353
Molecular Weight:: 51839.245 Da

References

Marchitti SA, Brocker C, Orlicky DJ, Vasiliou V: Molecular characterization, expression analysis, and role of ALDH3B1 in the cellular protection against oxidative stress. Free Radic Biol Med. 2010 Nov 15;49(9):1432-43. doi: 10.1016/j.freeradbiomed.2010.08.004. Epub 2010 Aug 10. [20699116 ]
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 ]
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 ]

Target Details

3. Aldehyde dehydrogenase, mitochondrial

General Function:: Electron carrier activity
Specific Function:: Not Available
Gene Name:: ALDH2
Uniprot ID:: P05091
Molecular Weight:: 56380.93 Da

References

Yoval-Sanchez B, Rodriguez-Zavala JS: Differences in susceptibility to inactivation of human aldehyde dehydrogenases by lipid peroxidation byproducts. Chem Res Toxicol. 2012 Mar 19;25(3):722-9. doi: 10.1021/tx2005184. Epub 2012 Feb 29. [22339434 ]
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 ]
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 ]

Target Details

4. Alpha-enolase

General Function:: Transcription factor activity, sequence-specific dna binding
Specific Function:: Multifunctional enzyme that, as well as its role in glycolysis, plays a part in various processes such as growth control, hypoxia tolerance and allergic responses. May also function in the intravascular and pericellular fibrinolytic system due to its ability to serve as a receptor and activator of plasminogen on the cell surface of several cell-types such as leukocytes and neurons. Stimulates immunoglobulin production.MBP1 binds to the myc promoter and acts as a transcriptional repressor. May be a tumor suppressor.
Gene Name:: ENO1
Uniprot ID:: P06733
Molecular Weight:: 47168.555 Da

References

Reed TT, Pierce WM, Markesbery WR, Butterfield DA: Proteomic identification of HNE-bound proteins in early Alzheimer disease: Insights into the role of lipid peroxidation in the progression of AD. Brain Res. 2009 Jun 5;1274:66-76. doi: 10.1016/j.brainres.2009.04.009. Epub 2009 Apr 15. [19374891 ]
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 ]
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 ]

Target Details

5. Apolipoprotein A-I

General Function:: Phospholipid transporter activity
Specific Function:: Participates in the reverse transport of cholesterol from tissues to the liver for excretion by promoting cholesterol efflux from tissues and by acting as a cofactor for the lecithin cholesterol acyltransferase (LCAT). As part of the SPAP complex, activates spermatozoa motility.
Gene Name:: APOA1
Uniprot ID:: P02647
Molecular Weight:: 30777.58 Da

References

Szapacs ME, Kim HY, Porter NA, Liebler DC: Identification of proteins adducted by lipid peroxidation products in plasma and modifications of apolipoprotein A1 with a novel biotinylated phospholipid probe. J Proteome Res. 2008 Oct;7(10):4237-46. doi: 10.1021/pr8001222. Epub 2008 Sep 9. [18778096 ]
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 ]
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 ]

Target Details

6. Dihydropyrimidinase-related protein 2

General Function:: Dihydropyrimidinase activity
Specific Function:: Plays a role in neuronal development and polarity, as well as in axon growth and guidance, neuronal growth cone collapse and cell migration. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. May play a role in endocytosis.
Gene Name:: DPYSL2
Uniprot ID:: Q16555
Molecular Weight:: 62293.135 Da

References

Reed TT, Pierce WM, Markesbery WR, Butterfield DA: Proteomic identification of HNE-bound proteins in early Alzheimer disease: Insights into the role of lipid peroxidation in the progression of AD. Brain Res. 2009 Jun 5;1274:66-76. doi: 10.1016/j.brainres.2009.04.009. Epub 2009 Apr 15. [19374891 ]
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 ]
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 ]

Target Details

7. Glutathione S-transferase P

General Function:: S-nitrosoglutathione binding
Specific Function:: Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.
Gene Name:: GSTP1
Uniprot ID:: P09211
Molecular Weight:: 23355.625 Da

References

van Iersel ML, Ploemen JP, Lo Bello M, Federici G, van Bladeren PJ: Interactions of alpha, beta-unsaturated aldehydes and ketones with human glutathione S-transferase P1-1. Chem Biol Interact. 1997 Dec 12;108(1-2):67-78. [9463521 ]
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 ]
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 ]

Target Details

8. Multidrug resistance-associated protein 1

General Function:: Transporter activity
Specific Function:: Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics. Confers resistance to anticancer drugs. Hydrolyzes ATP with low efficiency.
Gene Name:: ABCC1
Uniprot ID:: P33527
Molecular Weight:: 171589.5 Da

References

Sultana R, Butterfield DA: Oxidatively modified GST and MRP1 in Alzheimer's disease brain: implications for accumulation of reactive lipid peroxidation products. Neurochem Res. 2004 Dec;29(12):2215-20. [15672542 ]
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 ]
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 ]

Target Details

9. NAD-dependent protein deacetylase sirtuin-3, mitochondrial

General Function:: Zinc ion binding
Specific Function:: NAD-dependent protein deacetylase. Activates or deactivates mitochondrial target proteins by deacetylating key lysine residues. Known targets include ACSS1, IDH, GDH, SOD2, PDHA1, LCAD, SDHA and the ATP synthase subunit ATP5O. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.
Gene Name:: SIRT3
Uniprot ID:: Q9NTG7
Molecular Weight:: 43572.71 Da

References

Fritz KS, Galligan JJ, Smathers RL, Roede JR, Shearn CT, Reigan P, Petersen DR: 4-Hydroxynonenal inhibits SIRT3 via thiol-specific modification. Chem Res Toxicol. 2011 May 16;24(5):651-62. doi: 10.1021/tx100355a. Epub 2011 Apr 14. [21449565 ]
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 ]
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 ]

Target Details

10. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1

General Function:: Phosphothreonine binding
Specific Function:: Peptidyl-prolyl cis/trans isomerase (PPIase) that binds to and isomerizes specific phosphorylated Ser/Thr-Pro (pSer/Thr-Pro) motifs in a subset of proteins, resulting in conformational changes in the proteins (PubMed:21497122, PubMed:22033920). Displays a preference for an acidic residue N-terminal to the isomerized proline bond. Regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Down-regulates kinase activity of BTK (PubMed:16644721). Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation (PubMed:15664191). Binds and targets PML and BCL6 for degradation in a phosphorylation-dependent manner (PubMed:17828269). Acts as a regulator of JNK cascade by binding to phosphorylated FBXW7, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation: degradation of FBXW7 leads to subsequent stabilization of JUN (PubMed:22608923).
Gene Name:: PIN1
Uniprot ID:: Q13526
Molecular Weight:: 18243.13 Da

References

Aluise CD, Rose K, Boiani M, Reyzer ML, Manna JD, Tallman K, Porter NA, Marnett LJ: Peptidyl-prolyl cis/trans-isomerase A1 (Pin1) is a target for modification by lipid electrophiles. Chem Res Toxicol. 2013 Feb 18;26(2):270-9. doi: 10.1021/tx300449g. Epub 2012 Dec 24. [23231502 ]
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 ]
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 ]

Target Details

11. Scavenger receptor class B member 1

General Function:: Virus receptor activity
Specific Function:: Receptor for different ligands such as phospholipids, cholesterol ester, lipoproteins, phosphatidylserine and apoptotic cells. Probable receptor for HDL, located in particular region of the plasma membrane, called caveolae. Facilitates the flux of free and esterified cholesterol between the cell surface and extracellular donors and acceptors, such as HDL and to a lesser extent, apoB-containing lipoproteins and modified lipoproteins. Probably involved in the phagocytosis of apoptotic cells, via its phosphatidylserine binding activity. Receptor for hepatitis C virus glycoprotein E2. Binding between SCARB1 and E2 was found to be independent of the genotype of the viral isolate. Plays an important role in the uptake of HDL cholesteryl ester (By similarity).(Microbial infection) Acts as a receptor for hepatitis C virus in hepatocytes.
Gene Name:: SCARB1
Uniprot ID:: Q8WTV0
Molecular Weight:: 60877.385 Da

References

Sticozzi C, Belmonte G, Pecorelli A, Arezzini B, Gardi C, Maioli E, Miracco C, Toscano M, Forman HJ, Valacchi G: Cigarette smoke affects keratinocytes SRB1 expression and localization via H2O2 production and HNE protein adducts formation. PLoS One. 2012;7(3):e33592. doi: 10.1371/journal.pone.0033592. Epub 2012 Mar 19. [22442701 ]
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 ]
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 ]

Target Details

12. Superoxide dismutase [Mn], mitochondrial

General Function:: Superoxide dismutase activity
Specific Function:: Destroys superoxide anion radicals which are normally produced within the cells and which are toxic to biological systems.
Gene Name:: SOD2
Uniprot ID:: P04179
Molecular Weight:: 24721.955 Da

References

Reed TT, Pierce WM, Markesbery WR, Butterfield DA: Proteomic identification of HNE-bound proteins in early Alzheimer disease: Insights into the role of lipid peroxidation in the progression of AD. Brain Res. 2009 Jun 5;1274:66-76. doi: 10.1016/j.brainres.2009.04.009. Epub 2009 Apr 15. [19374891 ]
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 ]
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 ]

Target Details

13. Triosephosphate isomerase

General Function:: Ubiquitin protein ligase binding
Specific Function:: Not Available
Gene Name:: TPI1
Uniprot ID:: P60174
Molecular Weight:: 30790.785 Da

References

Reed TT, Pierce WM, Markesbery WR, Butterfield DA: Proteomic identification of HNE-bound proteins in early Alzheimer disease: Insights into the role of lipid peroxidation in the progression of AD. Brain Res. 2009 Jun 5;1274:66-76. doi: 10.1016/j.brainres.2009.04.009. Epub 2009 Apr 15. [19374891 ]
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 ]
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 ]

Target Details

14. Klotho

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

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 ]
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 ]

Target Details

15. NADPH oxidase 4

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

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 ]
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 ]

Target Details

16. Solute carrier family 22 member 8

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

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 ]
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 ]

4-Hydroxynonenal (T3D4180)

Structure for T3D4180: 4-Hydroxynonenal

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