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Record Information
Version2.0
Creation Date2014-08-29 05:48:06 UTC
Update Date2014-12-24 20:26:40 UTC
Accession NumberT3D4161
Identification
Common NameHomocysteine
ClassSmall Molecule
DescriptionHomocysteine 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. Homocysteine is a sulfur-containing amino acid that arises during methionine metabolism. Although its concentration in plasma is only about 10 micromolar (uM), even moderate hyperhomocysteinemia is associated with increased incidence of cardiovascular disease and Alzheimer's disease. Elevations in plasma homocysteine are commonly found as a result of vitamin deficiencies, polymorphisms of enzymes of methionine metabolism, and renal disease. Pyridoxal, folic acid, riboflavin, and Vitamin B(12) are all required for methionine metabolism, and deficiency of each of these vitamins result in elevated plasma homocysteine. A polymorphism of methylenetetrahydrofolate reductase (C677T), which is quite common in most populations with a homozygosity rate of 10-15 %, is associated with moderate hyperhomocysteinemia, especially in the context of marginal folate intake. Plasma homocysteine is inversely related to plasma creatinine in patients with renal disease. This is due to an impairment in homocysteine removal in renal disease. Homocysteine is an independent cardiovascular disease (CVD) risk factor modifiable by nutrition and possibly exercise. Homocysteine was first identified as an important biological compound in 1932 and linked with human disease in 1962 when elevated urinary homocysteine levels were found in children with mental retardation. This condition, called homocysteinuria, was later associated with premature occlusive CVD, even in children. These observations led to research investigating the relationship of elevated homocysteine levels and CVD in a wide variety of populations including middle age and elderly men and women with and without traditional risk factors for CVD. (1, 2).
Compound Type
  • Amine
  • Metabolite
  • Natural Compound
  • Organic Compound
  • Uremic Toxin
Chemical Structure
Thumb
Synonyms
Synonym
(+-)-homocysteine
(S)-2-amino-4-mercapto-Butanoate
(S)-2-amino-4-mercapto-Butanoic acid
2-Amino-4-mercapto-Butanoate
2-Amino-4-mercapto-Butanoic acid
2-Amino-4-mercapto-Butyric acid
2-Amino-4-mercapto-DL-Butyrate
2-Amino-4-mercapto-DL-Butyric acid
2-Amino-4-mercaptobutyric acid
2-Amino-4-sulfanylbutanoate
2-Amino-4-sulfanylbutanoic acid
D,L-Homocysteine
DL-2-amino-4-mercapto-Butyric acid
DL-2-Amino-4-mercaptobutyric acid
DL-Homocysteine
DL-homocysteine (free base)
HCY
Homo-CYS
L-2-Amino-4-mercapto-Butyric acid
L-Homocysteine
Usaf B-12
Chemical FormulaC4H9NO2S
Average Molecular Mass135.185 g/mol
Monoisotopic Mass135.035 g/mol
CAS Registry Number454-29-5
IUPAC Name(2S)-2-amino-4-sulfanylbutanoic acid
Traditional NameL-homocysteine
SMILESNC(CCS)C(O)=O
InChI IdentifierInChI=1/C4H9NO2S/c5-3(1-2-8)4(6)7/h3,8H,1-2,5H2,(H,6,7)
InChI KeyInChIKey=FFFHZYDWPBMWHY-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as l-alpha-amino acids. These are alpha amino acids which have the L-configuration of the alpha-carbon atom.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentL-alpha-amino acids
Alternative Parents
Substituents
  • L-alpha-amino acid
  • Thia fatty acid
  • Fatty acid
  • Fatty acyl
  • Amino acid
  • Alkylthiol
  • Carboxylic acid
  • Monocarboxylic acid or derivatives
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Primary amine
  • Organosulfur compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organopnictogen compound
  • Primary aliphatic amine
  • Organic oxygen compound
  • Carbonyl group
  • Amine
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginEndogenous
Cellular Locations
  • Cytoplasm
  • Membrane
Biofluid LocationsNot Available
Tissue Locations
  • Adipose Tissue
  • Artery
  • Brain
  • Fibroblasts
  • Intestine
  • Kidney
  • Liver
  • Muscle
  • Nerve Cells
  • Neuron
  • Pancreas
  • Placenta
  • Platelet
Pathways
NameSMPDB LinkKEGG Link
Betaine MetabolismSMP00123 map00260
Catecholamine BiosynthesisSMP00012 map00350
Glycine and Serine MetabolismSMP00004 map00260
Homocysteine DegradationSMP00455 Not Available
Methionine MetabolismSMP00033 map00270
Cystathionine Beta-Synthase DeficiencySMP00177 Not Available
Homocystinuria due to defect of N(5,10)-methylene THF deficiencySMP00543 Not Available
Homocystinuria, cystathionine beta-synthase deficiencySMP00515 Not Available
Homocystinuria-megaloblastic anemia due to defect in cobalamin metabolism, cblG complementation typeSMP00570 Not Available
Methionine Adenosyltransferase DeficiencySMP00221 Not Available
Methylenetetrahydrofolate Reductase Deficiency (MTHFRD)SMP00340 Not Available
S-Adenosylhomocysteine (SAH) Hydrolase DeficiencySMP00214 Not Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point232 - 233°C
Boiling PointNot Available
Solubility148 mg/mL
LogPNot Available
Predicted Properties
PropertyValueSource
Water Solubility14.8 g/LALOGPS
logP-2.3ALOGPS
logP-2.6ChemAxon
logS-0.96ALOGPS
pKa (Strongest Acidic)2.46ChemAxon
pKa (Strongest Basic)9.41ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area63.32 ŲChemAxon
Rotatable Bond Count3ChemAxon
Refractivity32.94 m³·mol⁻¹ChemAxon
Polarizability13.54 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 (Non-derivatized)splash10-004i-0920000000-20fbffbe76510c066e6f2017-09-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0006-9000000000-1f800d28bca4b2b7a49f2016-09-22View 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 (TMS_1_2) - 70eV, PositiveNot Available2021-11-05View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_3) - 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_1_2) - 70eV, PositiveNot Available2021-11-05View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_1_3) - 70eV, PositiveNot Available2021-11-05View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-014l-4900000000-c50d79ba3a5013bcf29f2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-000i-9000000000-025c9e1f4fb58138c43b2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-014i-4900000000-33f205e002f49f0347642017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 35V, Positivesplash10-052r-0900000000-c1f98c8182b5ddc09cb12021-09-20View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00ko-9800000000-80a1c80328e8836233a42015-09-15View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0006-9100000000-1f611da44349ffdfaefe2015-09-15View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0bvi-9000000000-c9d62a66522e46a17f562015-09-15View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-001i-3900000000-e8322d5858cba16a3bd22015-09-15View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-00lr-6900000000-e0190a1cc33e605bac0a2015-09-15View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-001i-9000000000-900bb5d8fb11bec02e392015-09-15View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-001i-0900000000-38e427e24202b24115972021-09-21View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-001i-7900000000-5cf2133d9faac56032d32021-09-21View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-001i-9000000000-942ac689538269d6ca7b2021-09-21View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0006-9000000000-166428542631f9ac07142021-09-25View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0a4i-9000000000-9bcb57b924579a6c34112021-09-25View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a4j-9000000000-8eee886864db64f3eec22021-09-25View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, H2O, experimental)Not Available2019-05-22View Spectrum
1D NMR1H NMR Spectrum (1D, 400 MHz, D2O, experimental)Not Available2019-05-22View Spectrum
1D NMR1H NMR Spectrum (1D, D2O, experimental)Not Available2019-05-22View Spectrum
1D NMR13C NMR Spectrum (1D, D2O, experimental)Not Available2019-05-22View 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
1D NMR13C NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
2D NMR[1H, 13C]-HSQC NMR Spectrum (2D, 600 MHz, H2O, experimental)Not Available2019-05-22View Spectrum
Toxicity Profile
Route of ExposureEndogenous
Mechanism of ToxicityNitrosylation converts homocysteine (Hcy) into a methionine analogue, S-nitroso-Homocysteine, which can substitute for methionine in protein synthesis in biological systems. In humans, homocyteine-thiolactone modifies proteins posttranslationally by forming adducts in which homocysteine is linked by amide bonds to epsilon-amino group of protein lysine residues (Hcy-epsilonN-Lys-protein). Levels of homocystine bound by amide or peptide linkages (Homocysteine-N-protein) in human plasma proteins are directly related to plasma 'total homocysteine' levels. Homocysteine-N-hemoglobin and Homocysteine-N-albumin constitute a major pool of homocysteine in human blood, larger than 'total homocysteine' pool. Homocysteine-thiolactone is present in human plasma. Modification with Homocysteine-thiolactone leads to protein damage and induces immune response. Autoantibodies that specifically recognize the Homocysteine-epsilonN-Lys-epitope on Homocysteine-thiolactone-modified proteins occur in humans. The ability of Homocysteine to interfere with protein biosynthesis, which causes protein damage, induces cell death and elicits immune response, is likely a key contributor to the toxicity of homocysteine (26). Uremic toxins such as homocysteine 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) (4). 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 (5).
MetabolismIn the body, dietary methionine is converted to homocysteine. In a series of metabolic steps, the enzyme cystathionine b-synthase (CBS) irreversibly generates a substance called cystathionine from homocysteine. The rate at which homocysteine is generated from methionine and then converted to cystathionine is evidently determined by the habitual dietary intake of methionine. L-Homocysteine has two primary fates: conversion via tetrahydrofolate (THF) back into L-methionine or conversion to L-cysteine. Homocysteine can cyclize to give homocysteine thiolactone, a five-membered heterocycle, a reaction catalyzed by methionyl-transfer RNA synthetase.
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 LevelSerum levels > 15 µmol/L
Health EffectsChronically high levels of homocysteine (hyperhomocysteinemia) is associated with increased incidence of cardiovascular disease and Alzheimer's disease. Elevations in plasma homocysteine are commonly found as a result of vitamin deficiencies, polymorphisms of enzymes of methionine metabolism, and renal disease. Homocysteine is an independent cardiovascular disease (CVD) risk factor. This includes heart attack, stroke, peripheral atherosclerosis, and venous thromboembolism (the blockage of a blood vessel by a migrating clot). Furthermore, the risk associated with homocysteine appears to increase throughout the normal range of concentrations; each 1 micromolar rise in the concentration of homocysteine in the blood corresponds to an increase of about 10% in cardiovascular risk. A high level of homocysteine makes a person more prone to endothelial injury, which leads to vascular inflammation, which in turn may lead to atherogenesis, which can result in ischemic injury. High levels of homocysteine limit the early development of heart and blood vessel disease. High homocysteine is associated with low levels of vitamin B6, B12, and folate and renal disease .Chronically high levels of homocysteine are associated with at least 6 inborn errors of metabolism including: Cystathionine Beta-Synthase Deficiency, Homocystinuria due to defect of N(5,10)-methylene THF deficiency, Homocystinuria-megaloblastic anemia due to defect in cobalamin metabolism, Methionine Adenosyltransferase Deficiency, Methylenetetrahydrofolate reductase deficiency and S-Adenosylhomocysteine (SAH) Hydrolase Deficiency. Homocystinuria is characterized by about 20-fold incrase over the normal concentration—is associated with greatly increased risk for premature vascular disease, sometimes leading to strokes or heart attacks in teenagers.
SymptomsModerately high levels of homocysteine produce no overt symptoms. Extremely high levels in adults over extended periods of times can lead to the usual symptoms of heart disease (high blood pressure, atherosclerosis, shortness of breath, poor exercise tolerance, etc.). Individuals with genetic forms of homocysteinuria experience such symptoms as dislocation of the lenses in the eyes, nearsightedness, abnormal blood clots, osteoporosis (weakening of the bones), learning disabilities and developmental problems. As a uremic toxin, high levels of homocysteine in adults 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.
TreatmentSeveral groups of investigators have reported a positive impact of supplementation with vitamins B6, B12, and folic acid, administered alone or jointly, in patients with homocystinuria. Folic acid appears to be useful in most subjects while very high doses of B6 (100 mg or more daily) also seem to have broad utility. The efficacy of supplemental B12 may likewise hinge on baseline B12 status. Lower homocysteine levels in people who eat breakfast cereals may reflect the fact that such cereals are frequently enriched with B vitamins. High intakes of betaine (6 grams or more daily) have been used successfully to treat genetic homocystinuria in humans.
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB04422
HMDB IDHMDB00742
PubChem Compound ID778
ChEMBL IDCHEMBL310604
ChemSpider ID757
KEGG IDC00155
UniProt IDNot Available
OMIM ID
ChEBI ID17230
BioCyc IDHOMO-CYS
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkHomocysteine
References
Synthesis ReferenceNot Available
MSDSLink
General References
  1. Joubert LM, Manore MM: Exercise, nutrition, and homocysteine. Int J Sport Nutr Exerc Metab. 2006 Aug;16(4):341-61. [17136938 ]
  2. Brosnan JT: Homocysteine and cardiovascular disease: interactions between nutrition, genetics and lifestyle. Can J Appl Physiol. 2004 Dec;29(6):773-80. [15630149 ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. Yu CK, Lakasing L, Papageorghiou AT, Spencer K, Nicolaides KH: Uterine artery Doppler and mid-trimester maternal plasma homocysteine in subsequent pre-eclampsia. J Matern Fetal Neonatal Med. 2004 Aug;16(2):134-9. [15512726 ]
  7. Giladi N, Mordechovich M, Gruendlinger L, Shabtai H, Merims D, Naor S, Baltadzhieva R, Hausdorff JM, Gur AY, Bornstein NM: "Brain Screen": A self-referral, screening program for strokes, falls and dementia risk factors. J Neurol. 2006 Mar;253(3):307-15. Epub 2005 Oct 10. [16208527 ]
  8. Terzolo M, Allasino B, Bosio S, Brusa E, Daffara F, Ventura M, Aroasio E, Sacchetto G, Reimondo G, Angeli A, Camaschella C: Hyperhomocysteinemia in patients with Cushing's syndrome. J Clin Endocrinol Metab. 2004 Aug;89(8):3745-51. [15292300 ]
  9. Laxdal E, Eide GE, Amundsen SR, Dregelid EB, Pedersen G, Jonung T, Aune S: Homocysteine levels, haemostatic risk factors and restenosis after carotid thrombendarterectomy. Eur J Vasc Endovasc Surg. 2004 Sep;28(3):323-8. [15288638 ]
  10. Akoglu B, Wondra K, Caspary WF, Faust D: Determinants of fasting total serum homocysteine levels in liver transplant recipients. Exp Clin Transplant. 2006 Jun;4(1):462-6. [16827644 ]
  11. Krantz JS, Mack WJ, Hodis HN, Liu CR, Liu CH, Kaufman FR: Early onset of subclinical atherosclerosis in young persons with type 1 diabetes. J Pediatr. 2004 Oct;145(4):452-7. [15480366 ]
  12. 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 ]
  13. Serot JM, Barbe F, Arning E, Bottiglieri T, Franck P, Montagne P, Nicolas JP: Homocysteine and methylmalonic acid concentrations in cerebrospinal fluid: relation with age and Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2005 Nov;76(11):1585-7. [16227558 ]
  14. Hershcovici T, Schechner V, Orlin J, Harell D, Beigel Y: Effect of different LDL-apheresis methods on parameters involved in atherosclerosis. J Clin Apher. 2004;19(2):90-7. [15274202 ]
  15. Muller T, Renger K, Kuhn W: Levodopa-associated increase of homocysteine levels and sural axonal neurodegeneration. Arch Neurol. 2004 May;61(5):657-60. [15148140 ]
  16. Eskes TK: Homocysteine and human reproduction. Clin Exp Obstet Gynecol. 2000;27(3-4):157-67. [11214939 ]
  17. Winkelmayer WC, Kramar R, Curhan GC, Chandraker A, Endler G, Fodinger M, Horl WH, Sunder-Plassmann G: Fasting plasma total homocysteine levels and mortality and allograft loss in kidney transplant recipients: a prospective study. J Am Soc Nephrol. 2005 Jan;16(1):255-60. Epub 2004 Nov 24. [15563562 ]
  18. Park BH, Kim YJ, Park JS, Lee HY, Ha EH, Min JW, Park HS: [Folate and homocysteine levels during pregnancy affect DNA methylation in human placenta]. J Prev Med Public Health. 2005 Nov;38(4):437-42. [16358830 ]
  19. Hossain GS, van Thienen JV, Werstuck GH, Zhou J, Sood SK, Dickhout JG, de Koning AB, Tang D, Wu D, Falk E, Poddar R, Jacobsen DW, Zhang K, Kaufman RJ, Austin RC: TDAG51 is induced by homocysteine, promotes detachment-mediated programmed cell death, and contributes to the cevelopment of atherosclerosis in hyperhomocysteinemia. J Biol Chem. 2003 Aug 8;278(32):30317-27. Epub 2003 May 8. [12738777 ]
  20. Schafer SA, Mussig K, Stefan N, Haring HU, Fritsche A, Balletshofer BM: Plasma homocysteine concentrations in young individuals at increased risk of type 2 diabetes are associated with subtle differences in glomerular filtration rate but not with insulin resistance. Exp Clin Endocrinol Diabetes. 2006 Jun;114(6):306-9. [16868889 ]
  21. Tchantchou F: Homocysteine metabolism and various consequences of folate deficiency. J Alzheimers Dis. 2006 Aug;9(4):421-7. [16917151 ]
  22. Siroka R, Trefil L, Rajdl D, Racek J, Rusnakova H, Cibulka R, Eiselt J, Filipovsky J: Asymmetric dimethylarginine, homocysteine and renal function--is there a relation? Clin Chem Lab Med. 2005;43(10):1147-50. [16197312 ]
  23. Onalan R, Onalan G, Gunenc Z, Karabulut E: Combining 2nd-trimester maternal serum homocysteine levels and uterine artery Doppler for prediction of preeclampsia and isolated intrauterine growth restriction. Gynecol Obstet Invest. 2006;61(3):142-8. Epub 2005 Dec 20. [16374017 ]
  24. Robinson G, Narasimhan S, Weatherall M, Beasley R: Raised plasma homocysteine levels in alcoholism: increasing the risk of heart disease and dementia? N Z Med J. 2005 Jun 3;118(1216):U1490. [15937525 ]
  25. Gulsen M, Yesilova Z, Bagci S, Uygun A, Ozcan A, Ercin CN, Erdil A, Sanisoglu SY, Cakir E, Ates Y, Erbil MK, Karaeren N, Dagalp K: Elevated plasma homocysteine concentrations as a predictor of steatohepatitis in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2005 Sep;20(9):1448-55. [16105135 ]
  26. Jakubowski H: Molecular basis of homocysteine toxicity in humans. Cell Mol Life Sci. 2004 Feb;61(4):470-87. [14999406 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Zinc ion binding
Specific Function:
Catalyzes the transfer of a methyl group from methyl-cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine. Subsequently, remethylates the cofactor using methyltetrahydrofolate (By similarity).
Gene Name:
MTR
Uniprot ID:
Q99707
Molecular Weight:
140525.91 Da
References
  1. Wolthers KR, Scrutton NS: Protein interactions in the human methionine synthase-methionine synthase reductase complex and implications for the mechanism of enzyme reactivation. Biochemistry. 2007 Jun 12;46(23):6696-709. Epub 2007 May 4. [17477549 ]
  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:
Metal ion binding
Specific Function:
Hydrolyzes N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA) which act as inhibitors of NOS. Has therefore a role in the regulation of nitric oxide generation.
Gene Name:
DDAH1
Uniprot ID:
O94760
Molecular Weight:
31121.5 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50640 uMNot AvailableBindingDB 50242405
References
  1. Hong L, Fast W: Inhibition of human dimethylarginine dimethylaminohydrolase-1 by S-nitroso-L-homocysteine and hydrogen peroxide. Analysis, quantification, and implications for hyperhomocysteinemia. J Biol Chem. 2007 Nov 30;282(48):34684-92. Epub 2007 Sep 24. [17895252 ]
  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 ]