T3DB: 3-Hydroxymethylglutaric acid

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (1)XML

Targets (1)

Record Information

Version

2.0

Creation Date

2014-08-29 06:09:33 UTC

Update Date

2018-03-21 17:46:13 UTC

Accession Number

T3D4262

Identification

Common Name

3-Hydroxymethylglutaric acid

Class

Small Molecule

Description

3-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. See less

Compound Type

Animal Toxin
Hypolipidemic Agent
Metabolite
Natural Compound
Organic Compound

Chemical Structure

MOL SDF 3D-SDF PDB SMILES InChI View 3D Structure

Synonyms

Show entries

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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

Showing 1 to 10 of 13 entries

Chemical Formula

C₆H₁₀O₅

Average Molecular Mass

162.141 g/mol

Monoisotopic Mass

162.053 g/mol

CAS Registry Number

503-49-1

IUPAC Name

3-hydroxy-3-methylpentanedioic acid

Traditional Name

meglutol

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 Key

InChIKey=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.

Kingdom

Organic compounds

Super Class

Lipids and lipid-like molecules

Class

Fatty Acyls

Sub Class

Fatty acids and conjugates

Direct Parent

Hydroxy 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 Framework

Aliphatic acyclic compounds

External Descriptors

tertiary alcohol (CHEBI:16831 )
dicarboxylic acid (CHEBI:16831 )
3-hydroxy carboxylic acid (CHEBI:16831 )

Biological Properties

Status

Detected and Not Quantified

Origin

Endogenous

Cellular Locations

Cytoplasm
Extracellular

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Name	SMPDB Link	KEGG Link
3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency	SMP00138	Not Available

Applications

Biological Roles

Chemical Roles

EC 1.1.1.34/EC 1.1.1.88 (hydroxymethylglutaryl-CoA reductase) inhibitor

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	105°C
Boiling Point	Not Available
Solubility	Not Available
LogP	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	275 g/L	ALOGPS
logP	-0.88	ALOGPS
logP	-0.75	ChemAxon
logS	0.23	ALOGPS
pKa (Strongest Acidic)	3.68	ChemAxon
pKa (Strongest Basic)	-3	ChemAxon
Physiological Charge	-2	ChemAxon
Hydrogen Acceptor Count	5	ChemAxon
Hydrogen Donor Count	3	ChemAxon
Polar Surface Area	94.83 Å²	ChemAxon
Rotatable Bond Count	4	ChemAxon
Refractivity	34.14 m³·mol⁻¹	ChemAxon
Polarizability	14.55 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
GC-MS	GC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (Non-derivatized)	splash10-0002-0930000000-67cdb23f1a51498bb80d	2014-06-16	View Spectrum
GC-MS	GC-MS Spectrum - GC-MS (3 TMS)	splash10-05nb-2950000000-10da019551eceff729ec	2014-06-16	View Spectrum
GC-MS	GC-MS Spectrum - EI-B (Non-derivatized)	splash10-0002-0960000000-75a1f0bc3ffb60117676	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Non-derivatized)	splash10-0002-0930000000-67cdb23f1a51498bb80d	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-MS (Non-derivatized)	splash10-05nb-2950000000-10da019551eceff729ec	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Non-derivatized)	splash10-0002-0920000000-77008c8c7fb6eb798e79	2017-09-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0udi-4900000000-ae0329f185525bab6028	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (3 TMS) - 70eV, Positive	splash10-0079-9253000000-af0bf7551c9147193ed4	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 GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_1) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_2) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_1) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_2) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TBDMS_1_1) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TBDMS_1_2) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TBDMS_2_1) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TBDMS_2_2) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TBDMS_3_1) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)	splash10-05fr-2900000000-d5b3d7ccc3617f392a63	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)	splash10-004i-9800000000-1a510972071bf02a23f7	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)	splash10-0kdi-9300000000-6afee652d0eb18e589c3	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negative	splash10-03di-0900000000-ae679b03ae8cdbc1cc40	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negative	splash10-0002-9300000000-8d7565d3b9cbed5d13ac	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Negative	splash10-0a4i-9000000000-d06ad8ce44567793a49d	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Negative	splash10-0a4i-9000000000-f3c4c2c0cb3ff49db482	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Negative	splash10-0a4i-9000000000-98c0337e0bebe4fefe6c	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) , Positive	splash10-01qa-2900000000-182405b2867309ab7df8	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) , Negative	splash10-03dj-5900000000-d9ffa79e6b62296f2626	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-03di-0900000000-2847ca367167b7cf107b	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0002-9300000000-f9ab44912911fd1e9ec7	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0a4i-9000000000-589bf77ae5f575911b64	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0a4i-9000000000-f3c4c2c0cb3ff49db482	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0a4i-9000000000-98c0337e0bebe4fefe6c	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , negative	splash10-03dj-5900000000-d9ffa79e6b62296f2626	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-01qa-2900000000-182405b2867309ab7df8	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Negative	splash10-0a4i-9000000000-f94de43a0b43873232bf	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Negative	splash10-0a4j-9300000000-9861bfd5df213d5b52e4	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0002-0900000000-a3631689983e6d6a3be7	2015-04-24	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-002b-2900000000-54e16eaede819dea2bdc	2015-04-24	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-000i-9600000000-31a4e319505eebd3d1d1	2015-04-24	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-03xr-2900000000-405383db70ec0564b916	2015-04-25	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-07bg-5900000000-dfc057320722ae1d926c	2015-04-25	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0a4m-9300000000-e5a720c14cbc5de82d4d	2015-04-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 500 MHz, H₂O, experimental)	Not Available	2012-12-04	View Spectrum
2D NMR	[¹H, ¹³C]-HSQC NMR Spectrum (2D, 600 MHz, H₂O, experimental)	Not Available	2012-12-05	View Spectrum

Toxicity Profile

Route of Exposure

Not Available

Mechanism of Toxicity

Not Available

Metabolism

Not Available

Toxicity Values

Not Available

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

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

Uses/Sources

This is an endogenously produced metabolite found in the human body. It is used in metabolic reactions, catabolic reactions or waste generation.

Minimum Risk Level

Not Available

Health Effects

Chronically high levels of 3-hydroxymethylglutaric acid are associated with the inborn error of metabolism: 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency.

Symptoms

Not Available

Treatment

Not Available

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

16831

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Not Available

PDB ID

MAH

ACToR ID

Not Available

Wikipedia Link

3-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.

MSDS

Link

General References

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 ]
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 ]
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 ]
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 ]
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 ]
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 ]
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 ]
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 ]
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 Genes

Not Available

Down-Regulated Genes

Not 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

Type	Value	Assay Type	Assay Source
Inhibitory	0.0235 uM	Not Available	BindingDB 50160720
IC50	4 uM	Not Available	BindingDB 50160720

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
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 ]
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 ]

3-Hydroxymethylglutaric acid (T3D4262)

Structure for T3D4262: 3-Hydroxymethylglutaric acid

Targets

Binding/Activity Constants

References