3-Hydroxymethylglutaric acid (T3D4262)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (1)XML
Targets (1)
Record Information
Version2.0
Creation Date2014-08-29 06:09:33 UTC
Update Date2018-03-21 17:46:13 UTC
Accession NumberT3D4262
Identification
Common Name3-Hydroxymethylglutaric acid
ClassSmall Molecule
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.
Compound Type
  • Animal Toxin
  • Hypolipidemic Agent
  • Metabolite
  • Natural Compound
  • Organic Compound
Chemical Structure
Thumb
MOLSDF3D-SDFPDBSMILESInChI View 3D Structure
Synonyms
Synonym
3-Hydroxy-3-methyl-Glutaric acid
3-Hydroxy-3-methylglutarate
3-Hydroxy-3-methylglutaric acid
3-Hydroxymethylglutarate
3-Methyl-3-hydroxyglutarate
3-Methyl-3-hydroxyglutaric acid
b-Hydroxy-b-methylglutarate
b-Hydroxy-b-methylglutaric acid
beta-Hydroxy-beta-methylglutarate
beta-Hydroxy-beta-methylglutaric acid
CB 337
Dicrotalate
Dicrotalic acid
Chemical FormulaC6H10O5
Average Molecular Mass162.141 g/mol
Monoisotopic Mass162.053 g/mol
CAS Registry Number503-49-1
IUPAC Name3-hydroxy-3-methylpentanedioic acid
Traditional Namemeglutol
SMILESCC(O)(CC(O)=O)CC(O)=O
InChI IdentifierInChI=1S/C6H10O5/c1-6(11,2-4(7)8)3-5(9)10/h11H,2-3H2,1H3,(H,7,8)(H,9,10)
InChI KeyInChIKey=NPOAOTPXWNWTSH-UHFFFAOYSA-N
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
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
Biological Properties
StatusDetected and Not Quantified
OriginEndogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
Biofluid LocationsNot Available
Tissue LocationsNot Available
Pathways
NameSMPDB LinkKEGG Link
3-Hydroxy-3-Methylglutaryl-CoA Lyase DeficiencySMP00138 Not Available
Applications
Biological Roles
Chemical Roles
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point105°C
Boiling PointNot Available
SolubilityNot Available
LogPNot 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 KeyDeposition DateView
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (Non-derivatized)splash10-0002-0930000000-67cdb23f1a51498bb80d2014-06-16View Spectrum
GC-MSGC-MS Spectrum - GC-MS (3 TMS)splash10-05nb-2950000000-10da019551eceff729ec2014-06-16View Spectrum
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0002-0960000000-75a1f0bc3ffb601176762017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0002-0930000000-67cdb23f1a51498bb80d2017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-05nb-2950000000-10da019551eceff729ec2017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0002-0920000000-77008c8c7fb6eb798e792017-09-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0udi-4900000000-ae0329f185525bab60282017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (3 TMS) - 70eV, Positivesplash10-0079-9253000000-af0bf7551c9147193ed42017-10-06View 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 (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_2_1) - 70eV, PositiveNot Available2021-11-05View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_2_2) - 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_2_1) - 70eV, PositiveNot Available2021-11-05View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_2_2) - 70eV, PositiveNot Available2021-11-05View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_3_1) - 70eV, PositiveNot Available2021-11-05View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)splash10-05fr-2900000000-d5b3d7ccc3617f392a632012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)splash10-004i-9800000000-1a510972071bf02a23f72012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)splash10-0kdi-9300000000-6afee652d0eb18e589c32012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negativesplash10-03di-0900000000-ae679b03ae8cdbc1cc402012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negativesplash10-0002-9300000000-8d7565d3b9cbed5d13ac2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Negativesplash10-0a4i-9000000000-d06ad8ce44567793a49d2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Negativesplash10-0a4i-9000000000-f3c4c2c0cb3ff49db4822012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Negativesplash10-0a4i-9000000000-98c0337e0bebe4fefe6c2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) , Positivesplash10-01qa-2900000000-182405b2867309ab7df82012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) , Negativesplash10-03dj-5900000000-d9ffa79e6b62296f26262012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-03di-0900000000-2847ca367167b7cf107b2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0002-9300000000-f9ab44912911fd1e9ec72017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0a4i-9000000000-589bf77ae5f575911b642017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0a4i-9000000000-f3c4c2c0cb3ff49db4822017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0a4i-9000000000-98c0337e0bebe4fefe6c2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , negativesplash10-03dj-5900000000-d9ffa79e6b62296f26262017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-01qa-2900000000-182405b2867309ab7df82017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 20V, Negativesplash10-0a4i-9000000000-f94de43a0b43873232bf2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 10V, Negativesplash10-0a4j-9300000000-9861bfd5df213d5b52e42021-09-20View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0002-0900000000-a3631689983e6d6a3be72015-04-24View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-002b-2900000000-54e16eaede819dea2bdc2015-04-24View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000i-9600000000-31a4e319505eebd3d1d12015-04-24View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-03xr-2900000000-405383db70ec0564b9162015-04-25View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-07bg-5900000000-dfc057320722ae1d926c2015-04-25View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4m-9300000000-e5a720c14cbc5de82d4d2015-04-25View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, H2O, experimental)Not Available2012-12-04View Spectrum
2D NMR[1H, 13C]-HSQC NMR Spectrum (2D, 600 MHz, H2O, experimental)Not Available2012-12-05View Spectrum
Toxicity Profile
Route of ExposureNot Available
Mechanism of ToxicityNot Available
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-hydroxymethylglutaric acid are associated with the inborn error of metabolism: 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency.
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB04377
HMDB IDHMDB00355
PubChem Compound ID1662
ChEMBL IDCHEMBL50444
ChemSpider ID1600
KEGG IDC03761
UniProt IDNot Available
OMIM ID
ChEBI ID16831
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDMAH
ACToR IDNot Available
Wikipedia Link3-Hydroxy-3-methylglutaric acid
References
Synthesis Reference

Luigi Turbanti, Giorgio Garzelli, “Process for preparation of 3-hydroxy-3-methyl-glutaric acid.” U.S. Patent US4966993, issued October, 1985.

MSDSLink
General References
  1. 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. [10916782 ]
  2. 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. [9658458 ]
  3. 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. [3063529 ]
  4. 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. [7479590 ]
  5. 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. [16330550 ]
  6. 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 ]
  7. 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. [947633 ]
  8. 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. [1956713 ]
  9. 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. [509721 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. 3-hydroxy-3-methylglutaryl-coenzyme A reductase
General Function:
Nadph binding
Specific Function:
Transmembrane glycoprotein that is the rate-limiting enzyme in cholesterol biosynthesis as well as in the biosynthesis of nonsterol isoprenoids that are essential for normal cell function including ubiquinone and geranylgeranyl proteins.
Gene Name:
HMGCR
Uniprot ID:
P04035
Molecular Weight:
97475.155 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.0235 uMNot AvailableBindingDB 50160720
IC504 uMNot AvailableBindingDB 50160720
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
  3. Medina-Franco JL, Lopez-Vallejo F, Rodriguez-Morales S, Castillo R, Chamorro G, Tamariz J: Molecular docking of the highly hypolipidemic agent alpha-asarone with the catalytic portion of HMG-CoA reductase. Bioorg Med Chem Lett. 2005 Feb 15;15(4):989-94. [15686898 ]