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Record Information
Creation Date2014-08-29 06:09:43 UTC
Update Date2018-03-21 17:46:13 UTC
Accession NumberT3D4263
Common Name3-Hydroxyisovaleric acid
ClassSmall Molecule
Description3-Hydroxyisovaleric acid is a normal human metabolite excreted in the urine. It is a byproduct of the leucine degradation pathway. Production of 3-hydroxyisovaleric acid begins with the conversion of 3-methylcrotonyl-CoA into 3-methylglutaconyl-CoA in the mitochondria by the biotin-dependent enzyme methylcrotonyl-CoA carboxylase. Biotin deficiencies, certain lifestyle habits (smoking), or specific genetic conditions can reduce methylcrotonyl-CoA carboxylase activity. This reduction can lead to a buildup of 3-methylcrotonyl-CoA, which is converted into 3-hydroxyisovaleryl-CoA by the enzyme enoyl-CoA hydratase. Increased concentrations of 3-methylcrotonyl-CoA and 3-hydroxyisovaleryl-CoA can lead to a disruption of the esterified CoA:free CoA ratio, and ultimately to mitochondrial toxicity. Detoxification of these metabolic end products occur via the transfer of the 3-hydroxyisovaleryl moiety to carnitine forming 3-hydroxyisovaleric acid-carnitine or 3HIA-carnitine, which is then transferred across the inner mitochondrial membrane where 3-hydroxyisovaleric acid is released as the free acid (PMID: 21918059). 3-Hydroxyisovaleric acid has been found to be elevated in smokers and in subjects undergoing long-term anticonvulsant therapy with carbamazepine and/or phenytoin. These levels are elevated due to impairment of renal reclamation of biotin. Levels may also be increased from prolonged consumption of raw egg-whites (PMID: 16895887, 9523856, 15447901, 9176832) (OMIM: 210210, 253270, 600529, 253260, 246450, 210200, 238331). When present in sufficiently high levels, 3-hydroxyisovaleric acid can act as an acidogen and a metabotoxin. An acidogen is an acidic compound that induces acidosis, which has multiple adverse effects on many organ systems. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of 3-hydroxyisovaleric acid are associated with at least a dozen inborn errors of metabolism, including 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, 3-methylglutaconic aciduria type I, biotinidase deficiency and isovaleric aciduria, dihydrolipoamide dehydrogenase deficiency, 3-methylcrotonyl-CoA carboxylase 1 deficiency, 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, late-onset multiple carboxylase deficiency, holocarboxylase synthetase deficiency, and 3-methylcrotonyl-CoA carboxylase 2 deficiency. 3-Hydroxyisovaleric acid is an organic acid. Abnormally high levels of organic acids in the blood (organic acidemia), urine (organic aciduria), the brain, and other tissues lead to general metabolic acidosis. Acidosis typically occurs when arterial pH falls below 7.35. In infants with acidosis, the initial symptoms include poor feeding, vomiting, loss of appetite, weak muscle tone (hypotonia), and lack of energy (lethargy). These can progress to heart, liver, and kidney abnormalities, seizures, coma, and possibly death. These are also the characteristic symptoms of the untreated IEMs mentioned above. Many affected children with organic acidemias experience intellectual disability or delayed development. In adults, acidosis or acidemia is characterized by headaches, confusion, feeling tired, tremors, sleepiness, and seizures.
Compound Type
  • Animal Toxin
  • Food Toxin
  • Metabolite
  • Natural Compound
  • Organic Compound
Chemical Structure
3-Hydroxy-3-methyl-Butanoic acid
3-Hydroxy-3-methyl-Butyric acid
3-Hydroxy-3-methylbutanoic acid
3-Hydroxy-3-methylbutyric acid
3-Hydroxy-isovaleric acid
3-OH-isovaleric acid
B-Hydroxy-b-methylbutyric acid
B-Hydroxyisovaleric acid
beta-Hydroxy-beta-methylbutyric acid
beta-Hydroxyisovaleric acid
Chemical FormulaC5H10O3
Average Molecular Mass118.131 g/mol
Monoisotopic Mass118.063 g/mol
CAS Registry Number625-08-1
IUPAC Name3-hydroxy-3-methylbutanoic acid
Traditional Name3-hydroxyisovaleric acid
InChI IdentifierInChI=1S/C5H10O3/c1-5(2,8)3-4(6)7/h8H,3H2,1-2H3,(H,6,7)
Chemical Taxonomy
Description belongs to the class of organic compounds known as hydroxy fatty acids. These are fatty acids in which the chain bears a hydroxyl group.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassFatty Acyls
Sub ClassFatty acids and conjugates
Direct ParentHydroxy fatty acids
Alternative Parents
  • Methyl-branched fatty acid
  • Short-chain hydroxy acid
  • Hydroxy fatty acid
  • Branched fatty acid
  • Tertiary alcohol
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Organic oxygen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Alcohol
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
Cellular Locations
  • Cytoplasm
  • Extracellular
Biofluid LocationsNot Available
Tissue Locations
  • Fibroblasts
3-Hydroxy-3-Methylglutaryl-CoA Lyase DeficiencySMP00138 Not Available
3-Methylglutaconic Aciduria Type ISMP00139 Not Available
Biotinidase DeficiencySMP00174 Not Available
Isovaleric AciduriaSMP00238 Not Available
ApplicationsNot Available
Biological Roles
Chemical RolesNot Available
Physical Properties
AppearanceWhite powder.
Experimental Properties
Melting Point65 - 67°C
Boiling PointNot Available
SolubilityNot Available
LogPNot Available
Predicted Properties
Water Solubility384 g/LALOGPS
pKa (Strongest Acidic)4.55ChemAxon
pKa (Strongest Basic)-2.7ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area57.53 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity28.1 m³·mol⁻¹ChemAxon
Polarizability11.75 ųChemAxon
Number of Rings0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectrum TypeDescriptionSplash KeyView
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (Non-derivatized)splash10-000t-0900000000-56f9e1ee9e19bacfc939JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-000t-0900000000-56f9e1ee9e19bacfc939JSpectraViewer | MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0a4i-9100000000-0809a885d114ba6b21d7JSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-0089-6910000000-3573bf97996ef7107955JSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)splash10-0a4i-9300000000-e715db06e575104deccdJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)splash10-0a4i-9000000000-885e3d959712c9998250JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)splash10-0avi-9800000000-f0296f537bd22b26f173JSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0ue9-5900000000-2f664d0b967c87e7358cJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0zn9-9500000000-233e5cd462b504c09d3cJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a4i-9000000000-62361f03b7c7a0d82bc4JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-00xr-9400000000-13e4ec512c0fde3123abJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-05tb-9200000000-96c7d7b3f54e7377a875JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0aba-9000000000-3cc71227974213e131c4JSpectraViewer
MSMass Spectrum (Electron Ionization)splash10-052f-9000000000-c15a37ad10e6379350aaJSpectraViewer | MoNA
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
2D NMR[1H,13C] 2D NMR SpectrumNot AvailableJSpectraViewer
Toxicity Profile
Route of ExposureNot Available
Mechanism of Toxicity3-Hydroxyisovaleric acid is a normal human metabolite excreted in the urine. Elevated levels of this compound are found in several disorders due to impairment of renal reclamation of biotin. Levels may also be increased from prolonged consumption of raw egg-whites.
MetabolismNot Available
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesThis is an endogenously produced metabolite found in the human body. It is used in metabolic reactions, catabolic reactions or waste generation.
Minimum Risk LevelNot Available
Health EffectsChronically high levels of 3-hydroxyisovaleric acid are associated with at least 4 inborn errors of metabolism including: 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency, 3-Methylglutaconic Aciduria Type I, Biotinidase deficiency and Isovaleric Aciduria.
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDNot Available
PubChem Compound ID69362
ChEMBL IDNot Available
ChemSpider ID62571
KEGG IDNot Available
UniProt IDNot Available
ChEBI ID37084
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkNot Available
Synthesis ReferenceRudney, Harry. Biosynthesis of b-hydroxy-b-methylglutaric acid. Journal of Biological Chemistry (1957), 227 363-77.
General References
  1. Stratton SL, Bogusiewicz A, Mock MM, Mock NI, Wells AM, Mock DM: Lymphocyte propionyl-CoA carboxylase and its activation by biotin are sensitive indicators of marginal biotin deficiency in humans. Am J Clin Nutr. 2006 Aug;84(2):384-8. [16895887 ]
  2. Mock DM, Mock NI, Nelson RP, Lombard KA: Disturbances in biotin metabolism in children undergoing long-term anticonvulsant therapy. J Pediatr Gastroenterol Nutr. 1998 Mar;26(3):245-50. [9523856 ]
  3. Sealey WM, Teague AM, Stratton SL, Mock DM: Smoking accelerates biotin catabolism in women. Am J Clin Nutr. 2004 Oct;80(4):932-5. [15447901 ]
  4. Mock DM, Stadler DD: Conflicting indicators of biotin status from a cross-sectional study of normal pregnancy. J Am Coll Nutr. 1997 Jun;16(3):252-7. [9176832 ]
  5. Amberg A, Rosner E, Dekant W: Biotransformation and kinetics of excretion of tert-amyl-methyl ether in humans and rats after inhalation exposure. Toxicol Sci. 2000 Jun;55(2):274-83. [10828258 ]
  6. Schurmann M, Engelbrecht V, Lohmeier K, Lenard HG, Wendel U, Gartner J: Cerebral metabolic changes in biotinidase deficiency. J Inherit Metab Dis. 1997 Nov;20(6):755-60. [9427142 ]
  7. Boulat O, Gradwohl M, Matos V, Guignard JP, Bachmann C: Organic acids in the second morning urine in a healthy Swiss paediatric population. Clin Chem Lab Med. 2003 Dec;41(12):1642-58. [14708889 ]
  8. 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 ]
  9. Jakobs C, Sweetman L, Nyhan WL, Packman S: Stable isotope dilution analysis of 3-hydroxyisovaleric acid in amniotic fluid: contribution to the prenatal diagnosis of inherited disorders of leucine catabolism. J Inherit Metab Dis. 1984;7(1):15-20. [6429435 ]
  10. Santer R, Muhle H, Suormala T, Baumgartner ER, Duran M, Yang X, Aoki Y, Suzuki Y, Stephani U: Partial response to biotin therapy in a patient with holocarboxylase synthetase deficiency: clinical, biochemical, and molecular genetic aspects. Mol Genet Metab. 2003 Jul;79(3):160-6. [12855220 ]
  11. Baykal T, Gokcay GH, Ince Z, Dantas MF, Fowler B, Baumgartner MR, Demir F, Can G, Demirkol M: Consanguineous 3-methylcrotonyl-CoA carboxylase deficiency: early-onset necrotizing encephalopathy with lethal outcome. J Inherit Metab Dis. 2005;28(2):229-33. [15877210 ]
  12. Rodriguez JM, Ruiz-Sala P, Ugarte M, Penalva MA: Fungal metabolic model for 3-methylcrotonyl-CoA carboxylase deficiency. J Biol Chem. 2004 Feb 6;279(6):4578-87. Epub 2003 Nov 11. [14612443 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available