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Record Information
Version4.0
StatusDetected and Quantified
Creation Date2005-11-16 15:48:42 UTC
Update Date2018-05-20 19:10:59 UTC
HMDB IDHMDB0000355
Secondary Accession Numbers
  • HMDB00355
Metabolite Identification
Common Name3-Hydroxymethylglutaric acid
Description3-Hydroxymethylglutaric acid is an "off-product" intermediate in the leucine degradation process. It is produced by defective or inefficient versions of 3-hydroxy-3-methylglutaryl-CoA lyase, an enzyme that normally catalyzes the conversion of 3-hydroxy-3-methylglutaryl-CoA to acetyl-CoA and acetoacetate. If this enzyme is defective, 3-hydroxy-3-methylglutaryl-CoA will accumulate in the mitochondria. Increased concentrations of 3-hydroxy-3-methylglutaryl-CoA can lead to a disruption of the esterified CoA:free CoA ratio and ultimately to mitochondrial toxicity. Detoxification of these CoA end products occurs via the transfer of the 3-hydroxymethylglutaryl moiety to carnitine, forming 3-hydroxymethylglutaric-carnitine, which is then transferred across the inner mitochondrial membrane where 3-hydroxymethylglutaric acid is released as the free acid. 3-Hydroxymethylglutaric acid has been found to accumulate in the urine of patients affected by 3-Hydroxy-3-methylglutaric aciduria, a rare inborn error of metabolism (OMIM: 246450 ). 3-Hydroxy-3-methylglutaric aciduria is caused by significantly reduced enzyme activity of the intramitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase (EC 4.1.3.4), the enzyme that catalyzes the final step of leucine degradation. This enzyme also plays a key role in ketone body formation. The profile of urinary organic acids for individuals with 3-hydroxy-3-methylglutaric aciduria is different from that of the other identified defects of leucine degradation, such as maple syrup urine disease (OMIM: 248600 ), isovaleric acidemia (OMIM: 243500 ), and methylcrotonylglycinemia (OMIM: 210200 ). The urinary organic acid profile of 3-hydroxy-3-methylglutaric aciduria includes elevated concentrations of 3-hydroxy-3-isovaleric, 3-hydroxy-3-methylglutaric, 3-methylglutaconic, and 3-methylglutaric acids (PMID: 10916782 , 9658458 , 3063529 ). Clinical manifestations of 3-hydroxy-3-methylglutaric aciduria include hepatomegaly, lethargy, coma, and apnea. Biochemically, there is a characteristic absence of ketosis with hypoglycemia, acidosis, hypertransaminasemia, and variable hyperammonemia. Therefore, when present in sufficiently high concentrations, 3-hydroxymethylglutaric 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. As noted above, chronically high levels of 3-hydroxymethylglutaric acid are associated with the inborn error of metabolism 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. 3-Hydroxymethylglutaric 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.
Structure
Thumb
Synonyms
ValueSource
(S)-3-Hydroxy-3-methylglutaric acidChEBI
(S)-MeglutolChEBI
3-HYDROXY-3-methyl-glutarIC ACIDChEBI
3-Hydroxy-3-methylpentanedioic acidChEBI
beta-Hydroxy-beta-methylglutaric acidChEBI
Dicrotalic acidChEBI
MeglutolChEBI
MeglutolumChEBI
(S)-3-Hydroxy-3-methylglutarateGenerator
3-HydroxymethylglutarateGenerator
3-HYDROXY-3-methyl-glutarateGenerator
3-Hydroxy-3-methylpentanedioateGenerator
b-Hydroxy-b-methylglutarateGenerator
b-Hydroxy-b-methylglutaric acidGenerator
beta-Hydroxy-beta-methylglutarateGenerator
β-hydroxy-β-methylglutarateGenerator
β-hydroxy-β-methylglutaric acidGenerator
DicrotalateGenerator
3-Hydroxy-3-methylglutarateHMDB
3-Hydroxy-3-methylglutaric acidHMDB
3-Methyl-3-hydroxyglutarateHMDB
3-Methyl-3-hydroxyglutaric acidHMDB
CB 337HMDB
3 Hydroxy 3 methylpentanedioic acidMeSH
Acid, 3-hydroxy-3-methylglutaricMeSH
Acid, 3-hydroxy-3-methylpentanedioicMeSH
beta Hydroxy beta methylglutarateMeSH
3 Hydroxy 3 methylglutaric acidMeSH
Chemical FormulaC6H10O5
Average Molecular Weight162.1406
Monoisotopic Molecular Weight162.05282343
IUPAC Name3-hydroxy-3-methylpentanedioic acid
Traditional Namemeglutol
CAS Registry Number503-49-1
SMILES
CC(O)(CC(O)=O)CC(O)=O
InChI Identifier
InChI=1S/C6H10O5/c1-6(11,2-4(7)8)3-5(9)10/h11H,2-3H2,1H3,(H,7,8)(H,9,10)
InChI KeyNPOAOTPXWNWTSH-UHFFFAOYSA-N
Chemical Taxonomy
DescriptionThis compound 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
Substituents
  • Methyl-branched fatty acid
  • Short-chain hydroxy acid
  • Hydroxy fatty acid
  • Branched fatty acid
  • Dicarboxylic acid or derivatives
  • Tertiary alcohol
  • 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
Ontology
Disposition

Route of exposure:

Source:

Biological location:

Process

Naturally occurring process:

Role

Indirect biological role:

Biological role:

Industrial application:

Physical Properties
StateSolid
Experimental Properties
PropertyValueReference
Melting Point105 °CNot Available
Boiling PointNot AvailableNot Available
Water SolubilityNot AvailableNot Available
LogPNot AvailableNot Available
Predicted Properties
PropertyValueSource
Water Solubility275 g/LALOGPS
logP-0.88ALOGPS
logP-0.75ChemAxon
logS0.23ALOGPS
pKa (Strongest Acidic)3.68ChemAxon
pKa (Strongest Basic)-3ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area94.83 ŲChemAxon
Rotatable Bond Count4ChemAxon
Refractivity34.14 m³·mol⁻¹ChemAxon
Polarizability14.55 ųChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (Non-derivatized)splash10-0002-0930000000-67cdb23f1a51498bb80dView in MoNA
GC-MSGC-MS Spectrum - GC-MS (3 TMS)splash10-05nb-2950000000-10da019551eceff729ecView in MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0002-0960000000-75a1f0bc3ffb60117676View in MoNA
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0002-0930000000-67cdb23f1a51498bb80dView in MoNA
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-05nb-2950000000-10da019551eceff729ecView in MoNA
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0002-0920000000-77008c8c7fb6eb798e79View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0udi-4900000000-ae0329f185525bab6028View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (3 TMS) - 70eV, Positivesplash10-0079-9253000000-af0bf7551c9147193ed4View in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)splash10-05fr-2900000000-d5b3d7ccc3617f392a63View in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)splash10-004i-9800000000-1a510972071bf02a23f7View in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)splash10-0kdi-9300000000-6afee652d0eb18e589c3View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negativesplash10-03di-0900000000-ae679b03ae8cdbc1cc40View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negativesplash10-0002-9300000000-8d7565d3b9cbed5d13acView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Negativesplash10-0a4i-9000000000-d06ad8ce44567793a49dView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Negativesplash10-0a4i-9000000000-f3c4c2c0cb3ff49db482View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Negativesplash10-0a4i-9000000000-98c0337e0bebe4fefe6cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) , Positivesplash10-01qa-2900000000-182405b2867309ab7df8View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) , Negativesplash10-03dj-5900000000-d9ffa79e6b62296f2626View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-03di-0900000000-2847ca367167b7cf107bView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0002-9300000000-f9ab44912911fd1e9ec7View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0a4i-9000000000-589bf77ae5f575911b64View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0a4i-9000000000-f3c4c2c0cb3ff49db482View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0a4i-9000000000-98c0337e0bebe4fefe6cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , negativesplash10-03dj-5900000000-d9ffa79e6b62296f2626View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-01qa-2900000000-182405b2867309ab7df8View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0002-0900000000-a3631689983e6d6a3be7View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-002b-2900000000-54e16eaede819dea2bdcView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000i-9600000000-31a4e319505eebd3d1d1View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-03xr-2900000000-405383db70ec0564b916View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-07bg-5900000000-dfc057320722ae1d926cView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4m-9300000000-e5a720c14cbc5de82d4dView in MoNA
1D NMR1H NMR SpectrumNot AvailableView in JSpectraViewer
2D NMR[1H,13C] 2D NMR SpectrumNot AvailableView in JSpectraViewer
Biological Properties
Cellular Locations
  • Cytoplasm (predicted from logP)
Biospecimen Locations
  • Feces
  • Saliva
  • Urine
Tissue LocationsNot Available
Pathways
Normal Concentrations
BiospecimenStatusValueAgeSexConditionReferenceDetails
FecesDetected but not Quantified Adult (>18 years old)Both
Normal
details
FecesDetected but not Quantified Adult (>18 years old)Both
Normal
details
SalivaDetected and Quantified0.0201 +/- 0.0639 uMAdult (>18 years old)Not Specified
Normal
    • Sugimoto et al. (...
details
SalivaDetected and Quantified0.0917 +/- 0.0851 uMAdult (>18 years old)Not Specified
Normal
    • Sugimoto et al. (...
details
UrineDetected and Quantified<200 umol/mmol creatinineAdult (>18 years old)FemaleNormal details
UrineDetected and Quantified2.6-4.5 umol/mmol creatinineAdult (>18 years old)FemaleNormal details
UrineDetected and Quantified6.788 +/- 4.222 umol/mmol creatinineChildren (1 - 13 years old)Not Specified
Normal
    • Mordechai, Hien, ...
details
UrineDetected but not Quantified Adult (>18 years old)Both
Normal
details
UrineDetected and Quantified27.0 (6.0-73.0) umol/mmol creatinineNewborn (0-30 days old)BothNormal
    • Geigy Scientific ...
details
UrineDetected and Quantified1.4 (0.7-3.0) umol/mmol creatinineAdult (>18 years old)BothNormal
    • Geigy Scientific ...
details
UrineDetected and Quantified3 (0-10) umol/mmol creatinineAdult (>18 years old)BothNormal details
UrineDetected and Quantified<50 umol/mmol creatinineNot SpecifiedNot SpecifiedNormal details
UrineDetected and Quantified2.4-3.6 umol/mmol creatinineAdult (>18 years old)MaleNormal details
UrineDetected and Quantified<31.61 umol/mmol creatinineChildren (1 - 18 years old)Both
Normal
    • BC Children's Hos...
details
UrineDetected and Quantified<200 umol/mmol creatinineNot SpecifiedNot SpecifiedNormal details
UrineDetected and Quantified2.8 (1.1 -5.8) umol/mmol creatinineAdult (>18 years old)Both
Normal
details
UrineDetected and Quantified28.1 (10.7-57.5) umol/mmol creatinineNewborn (0-30 days old)BothNormal details
UrineDetected and Quantified10.3 (4.3-31.4) umol/mmol creatinineChildren (1-13 years old)BothNormal details
UrineDetected and Quantified9.9 (5.7-14.4) umol/mmol creatinineChildren (1-13 years old)BothNormal details
UrineDetected and Quantified51.7 (13.1-101.1) umol/mmol creatinineInfant (0-1 year old)FemaleNormal details
UrineDetected and Quantified7.1 (2.2-24.5) umol/mmol creatinineAdolescent (13-18 years old)Not SpecifiedNormal details
UrineDetected and Quantified3.2(1.1-5.2) umol/mmol creatinineAdult (>18 years old)Both
Normal
details
UrineDetected and Quantified12.098 +/- 6.49 umol/mmol creatinineChildren (1 - 13 years old)Not Specified
Normal
    • Mordechai, Hien, ...
details
Abnormal Concentrations
BiospecimenStatusValueAgeSexConditionReferenceDetails
FecesDetected but not Quantified Adult (>18 years old)Both
Colorectal cancer
details
UrineDetected and Quantified481 umol/mmol creatinineAdult (>18 years old)Female3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency details
UrineDetected and Quantified1028.4 umol/mmol creatinineNewborn (0-30 days old)Male3-hydroxy-3-methylglutaric- coenzyme A lyase deficiency details
UrineDetected and Quantified10.581 +/- 10.628 umol/mmol creatinineChildren (1 - 13 years old)Not Specified
Eosinophilic esophagitis
    • Mordechai, Hien, ...
details
UrineDetected and Quantified1028.4 umol/mmol creatinineNewborn (0-30 days old)Male3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency details
UrineDetected and Quantified481 umol/mmol creatinineAdult (>18 years old)Female3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency details
UrineDetected and Quantified17.227 +/- 8.202 umol/mmol creatinineChildren (1 - 13 years old)Not Specified
Eosinophilic esophagitis
    • Mordechai, Hien, ...
details
UrineDetected and Quantified31.947 +/- 39.294 umol/mmol creatinineChildren (1 - 13 years old)Not Specified
Gastroesophageal reflux disease
    • Mordechai, Hien, ...
details
Associated Disorders and Diseases
Disease References
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency
  1. Bischof F, Nagele T, Wanders RJ, Trefz FK, Melms A: 3-hydroxy-3-methylglutaryl-CoA lyase deficiency in an adult with leukoencephalopathy. Ann Neurol. 2004 Nov;56(5):727-30. [PubMed:15505778 ]
  2. Santarelli F, Cassanello M, Enea A, Poma F, D'Onofrio V, Guala G, Garrone G, Puccinelli P, Caruso U, Porta F, Spada M: A neonatal case of 3-hydroxy-3-methylglutaric-coenzyme A lyase deficiency. Ital J Pediatr. 2013 May 24;39:33. doi: 10.1186/1824-7288-39-33. [PubMed:23705938 ]
  3. G.Frauendienst-Egger, Friedrich K. Trefz (2017). MetaGene: Metabolic & Genetic Information Center (MIC: http://www.metagene.de). METAGENE consortium.
Colorectal cancer
  1. Goedert JJ, Sampson JN, Moore SC, Xiao Q, Xiong X, Hayes RB, Ahn J, Shi J, Sinha R: Fecal metabolomics: assay performance and association with colorectal cancer. Carcinogenesis. 2014 Sep;35(9):2089-96. doi: 10.1093/carcin/bgu131. Epub 2014 Jul 18. [PubMed:25037050 ]
Eosinophilic esophagitis
  1. (). Mordechai, Hien, and David S. Wishart. .
Associated OMIM IDs
  • 114500 (Colorectal cancer)
  • 610247 (Eosinophilic esophagitis)
  • 246450 (3-Hydroxy-3-methylglutaryl-CoA lyase deficiency)
DrugBank IDDB04377
Phenol Explorer Compound IDNot Available
FoodDB IDFDB005950
KNApSAcK IDC00001187
Chemspider ID1600
KEGG Compound IDC03761
BioCyc IDCPD-547
BiGG IDNot Available
Wikipedia LinkNot Available
METLIN ID5344
PubChem Compound1662
PDB IDMAH
ChEBI ID16831
References
Synthesis ReferenceKlosterman, Harold J.; Smith, F. The isolation of b-hydroxy-b-methylglutaric acid from the seed of flax (Linum usitatissimum). Journal of the American Chemical Society (1954), 76 1229-30.
Material Safety Data Sheet (MSDS)Download (PDF)
General References
  1. Fu Z, Runquist JA, Forouhar F, Hussain M, Hunt JF, Miziorko HM, Kim JJ: Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights into catalysis and the molecular basis for hydroxymethylglutaric aciduria. J Biol Chem. 2006 Mar 17;281(11):7526-32. Epub 2005 Dec 5. [PubMed:16330550 ]
  2. 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. [PubMed:8087979 ]
  3. Mitchell GA, Jakobs C, Gibson KM, Robert MF, Burlina A, Dionisi-Vici C, Dallaire L: Molecular prenatal diagnosis of 3-hydroxy-3-methylglutaryl CoA lyase deficiency. Prenat Diagn. 1995 Aug;15(8):725-9. [PubMed:7479590 ]
  4. Wysocki SJ, Wilkinson SP, Hahnel R, Wong CY, Panegyres PK: 3-Hydroxy-3-methylglutaric aciduria, combined with 3-methylglutaconic aciduria. Clin Chim Acta. 1976 Aug 2;70(3):399-406. [PubMed:947633 ]
  5. Tuchman M, McCann MT, Johnson PE, Lemieux B: Screening newborns for multiple organic acidurias in dried filter paper urine samples: method development. Pediatr Res. 1991 Oct;30(4):315-21. [PubMed:1956713 ]
  6. Truscott RJ, Halpern B, Wysocki SJ, Hahnel R, Wilcken B: Studies on a child suspected of having a dficiency in 3-hydroxy-3-methylglutaryl-Co A lyase. Clin Chim Acta. 1979 Jul 2;95(1):11-16. [PubMed:509721 ]
  7. Koling S, Kalhoff H, Schauerte P, Lehnert W, Diekmann L: [3-hydroxy-3-methylglutaraciduria (case report of a female Turkish sisters with 3-hydroxy-3- methylglutaryl-Coenzyme A lyase deficiency]. Klin Padiatr. 2000 May-Jun;212(3):113-6. [PubMed:10916782 ]
  8. Eiris J, Ribes A, Fernandez-Prieto R, Rodriguez-Garcia J, Rodriguez-Segade S, Castro-Gago M: [3-hydroxy-3-methylglutaric aciduria and recurrent Reye-like syndrome]. Rev Neurol. 1998 Jun;26(154):911-4. [PubMed:9658458 ]
  9. Gibson KM, Breuer J, Nyhan WL: 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients. Eur J Pediatr. 1988 Dec;148(3):180-6. [PubMed:3063529 ]

Enzymes

General function:
Involved in catalytic activity
Specific function:
Key enzyme in ketogenesis (ketone body formation). Terminal step in leucine catabolism.
Gene Name:
HMGCL
Uniprot ID:
P35914
Molecular weight:
34359.84