T3DB: Methylmalonic acid

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation XML

Record Information

Version

2.0

Creation Date

2014-08-29 06:51:02 UTC

Update Date

2018-03-21 17:46:12 UTC

Accession Number

T3D4404

Identification

Common Name

Methylmalonic acid

Class

Small Molecule

Description

Methylmalonic acid is a malonic acid derivative, which is a vital intermediate in the metabolism of fat and protein. In particular, the coenzyme A-linked form of methylmalonic acid, methylmalonyl-CoA, is converted into succinyl-CoA by methylmalonyl-CoA mutase in a reaction that requires vitamin B12 as a cofactor. In this way, methylmalonic acid enters the Krebs cycle and is thus part of one of the anaplerotic reactions. Abnormalities in methylmalonic acid metabolism lead to methylmalonic aciduria. This inborn error of metabolism is attributed to a block in the enzymatic conversion of methylmalonyl CoA to succinyl CoA. Methylmalonic acid is also found to be associated with other inborn errors of metabolism, including cobalamin deficiency, cobalamin malabsorption, malonyl-CoA decarboxylase deficiency, and transcobalamin II deficiency. When present in sufficiently high levels, methylmalonic 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 methylmalonic acid are associated with at least 5 inborn errors of metabolism, including Malonyl CoA decarboxylase deficiency, Malonic Aciduria, Methylmalonate Semialdehyde Dehydrogenase Deficiency, Methylmalonic Aciduria and Methylmalonic Aciduria Due to Cobalamin-Related Disorders. Methylmalonic acid is an organic acid and 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 abnormalities, kidney abnormalities, liver damage, 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

MOL SDF PDB SMILES InChI

Synonyms

Synonym
1,1-Ethanedicarboxylate
1,1-Ethanedicarboxylic acid
2-Methylmalonate
2-Methylmalonic acid
Isosuccinate
Isosuccinic acid
Methyl-Malonate
Methyl-Malonic acid
Methyl-Propanedioate
Methyl-Propanedioic acid
Methylmalonate
Methylpropanedioate
Methylpropanedioic acid

Chemical Formula

C₄H₆O₄

Average Molecular Mass

118.088 g/mol

Monoisotopic Mass

118.027 g/mol

CAS Registry Number

516-05-2

IUPAC Name

2-methylpropanedioic acid

Traditional Name

methylmalonic acid

SMILES

CC(C(O)=O)C(O)=O

InChI Identifier

InChI=1S/C4H6O4/c1-2(3(5)6)4(7)8/h2H,1H3,(H,5,6)(H,7,8)

InChI Key

InChIKey=ZIYVHBGGAOATLY-UHFFFAOYSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as dicarboxylic acids and derivatives. These are organic compounds containing exactly two carboxylic acid groups.

Kingdom

Organic compounds

Super Class

Organic acids and derivatives

Class

Carboxylic acids and derivatives

Sub Class

Dicarboxylic acids and derivatives

Direct Parent

Dicarboxylic acids and derivatives

Alternative Parents

Substituents

1,3-dicarbonyl compound
Dicarboxylic acid or derivatives
Carboxylic acid
Organic oxygen compound
Organic oxide
Hydrocarbon derivative
Organooxygen compound
Carbonyl group
Aliphatic acyclic compound

Molecular Framework

Aliphatic acyclic compounds

External Descriptors

C4-dicarboxylic acid (CHEBI:30860 )
Dicarboxylic acids (LMFA01170118 )

Biological Properties

Status

Detected and Not Quantified

Origin

Endogenous

Cellular Locations

Cytoplasm
Extracellular

Biofluid Locations

Not Available

Tissue Locations

Kidney
Liver

Pathways

Name	SMPDB Link	KEGG Link
Propanoate Metabolism	SMP00016	map00640
Valine, Leucine and Isoleucine Degradation	SMP00032	map00280
Malonyl-coa decarboxylase deficiency	SMP00502	Not Available
Malonic Aciduria	SMP00198	Not Available
Methylmalonate Semialdehyde Dehydrogenase Deficiency	SMP00384	Not Available
Methylmalonic Aciduria	SMP00200	Not Available
Methylmalonic Aciduria Due to Cobalamin-Related Disorders	SMP00201	Not Available

Applications

Not Available

Biological Roles

human metabolite

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	135°C
Boiling Point	Not Available
Solubility	679.0 mg/mL
LogP	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	149 g/L	ALOGPS
logP	0.17	ALOGPS
logP	0.21	ChemAxon
logS	0.1	ALOGPS
pKa (Strongest Acidic)	2.48	ChemAxon
Physiological Charge	-2	ChemAxon
Hydrogen Acceptor Count	4	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	74.6 Å²	ChemAxon
Rotatable Bond Count	2	ChemAxon
Refractivity	23.56 m³·mol⁻¹	ChemAxon
Polarizability	10.06 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) (2 TMS)	splash10-0002-1910000000-cf95dd8a481761a28664	2014-06-16	View Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (2 TMS)	splash10-006t-8900000000-4d8795e7e4300cc7ceff	2014-06-16	View Spectrum
GC-MS	GC-MS Spectrum - GC-MS (2 TMS)	splash10-00lr-5940000000-56b86ada220d335ce30a	2014-06-16	View Spectrum
GC-MS	GC-MS Spectrum - GC-MS (3 TMS)	splash10-001i-9301000000-54e5247d046de566ac1e	2014-06-16	View Spectrum
GC-MS	GC-MS Spectrum - EI-B (Non-derivatized)	splash10-004i-9000000000-b9ee59dddf90dfc7c461	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Non-derivatized)	splash10-0002-1910000000-cf95dd8a481761a28664	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Non-derivatized)	splash10-006t-8900000000-4d8795e7e4300cc7ceff	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-MS (Non-derivatized)	splash10-001i-9301000000-54e5247d046de566ac1e	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-MS (Non-derivatized)	splash10-00lr-5940000000-56b86ada220d335ce30a	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Non-derivatized)	splash10-0002-0900000000-684a11ce99cccbd9194a	2017-09-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0g4i-9400000000-baa4ea6d613ebb8bffc7	2016-09-22	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positive	splash10-00dr-9310000000-a99f1bb4adbde62446d9	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 (TMS_1_1) - 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_2_1) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 10V, Negative (Annotated)	splash10-00di-9000000000-1578bea9a6b8b12e2f9b	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 25V, Negative (Annotated)	splash10-05fr-9000000000-0e443f81ee9c6c9b1fa5	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 40V, Negative (Annotated)	splash10-0ab9-9100000000-d23d6a0a35141ed9a950	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negative	splash10-01b9-6900000000-6d969044a89f00e1b46f	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negative	splash10-00di-9000000000-0f655174050263224e67	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Negative	splash10-0ab9-9000000000-26a654fb133b28a816a0	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Negative	splash10-0a4i-9000000000-7afd566e443d5fa38887	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Negative	splash10-0a4i-9000000000-5c4795e954d5c3e9b74e	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-01b9-6900000000-6d969044a89f00e1b46f	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-00di-9000000000-0f655174050263224e67	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0ab9-9000000000-26a654fb133b28a816a0	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0a4i-9000000000-7afd566e443d5fa38887	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0a4i-9000000000-5c4795e954d5c3e9b74e	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Negative	splash10-0a4i-9000000000-175b62a78de8d2295d7c	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-00dm-9100000000-2118d1ea1507076c595c	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Positive	splash10-0007-9000000000-5ead13e9a754843f3de4	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Negative	splash10-00di-9000000000-04818c3d6cdaf0e910eb	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Positive	splash10-052f-9000000000-ea4a508808f00639e8c2	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-0002-9100000000-e8e132c8d454aa8a0490	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-014i-5900000000-9b75ec910fa494f0ad6a	2016-09-12	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-05di-9200000000-87a71ae13cf70d990bb1	2016-09-12	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-004i-9000000000-e7ae04912b5ee745a992	2016-09-12	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-014i-4900000000-0714f0bc5c29e5d61ac4	2016-09-12	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-00di-9100000000-ecfebddbd3d8f7224994	2016-09-12	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-05fr-9000000000-506ee5ec2100e13e09ce	2016-09-12	View Spectrum
MS	Mass Spectrum (Electron Ionization)	splash10-05di-9000000000-8d09b408489f7b1743b5	2014-09-20	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 500 MHz, H₂O, experimental)	Not Available	2012-12-04	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 125 MHz, H₂O, experimental)	Not Available	2012-12-04	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, DMSO-d6, experimental)	Not Available	2014-09-20	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 22.53 MHz, DMSO-d6, experimental)	Not Available	2014-09-23	View Spectrum
1D NMR	¹H NMR Spectrum (1D, D₂O, experimental)	Not Available	2016-10-22	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, D₂O, experimental)	Not Available	2016-10-22	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 400 MHz, H₂O, experimental)	Not Available	2021-10-10	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

Methylmalonic acid is a vital intermediate in the metabolism of fat and protein. Abnormalities in methylmalonic acid metabolism lead to methylmalonic aciduria. This metabolic disease is attributed to a block in the enzymatic conversion of methylmalonyl CoA to succinyl CoA. Accumulation of Methylmalonic acid in the body has been shown to be toxic.

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 methylmalonic acid are associated with at least 5 inborn errors of metabolism including: Malonyl CoA decarboxylase deficiency, Malonic Aciduria, Methylmalonate Semialdehyde Dehydrogenase Deficiency, Methylmalonic Aciduria and Methylmalonic Aciduria Due to Cobalamin-Related Disorders.

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

30860

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Not Available

PDB ID

DXX

ACToR ID

Not Available

Wikipedia Link

Methylmalonic acid

References

Synthesis Reference

Not Available

MSDS

T3D4404.pdf

General References

van Asselt DZ, Karlietis MH, Poels PJ, de Jong JG, Wevers RA, Hoefnagels WH: Cerebrospinal fluid methylmalonic acid concentrations in neurological patients with low and normal serum cobalamin concentrations. Acta Neurol Scand. 1998 Jun;97(6):413-6. [9669477 ]
Magera MJ, Helgeson JK, Matern D, Rinaldo P: Methylmalonic acid measured in plasma and urine by stable-isotope dilution and electrospray tandem mass spectrometry. Clin Chem. 2000 Nov;46(11):1804-10. [11067816 ]
Nakamura E, Rosenberg LE, Tanaka K: Microdetermination of methylmalonic acid and other short chain dicarboxylic acids by gas chromatography: use in prenatal diagnosis of methylmalonic acidemia and in studies of isovaleric acidemia. Clin Chim Acta. 1976 Apr 15;68(2):127-40. [1261058 ]
Jakobs C, Sweetman L, Nyhan WL: Hydroxy acid metabolites of branched-chain amino acids in amniotic fluid. Clin Chim Acta. 1984 Jul 16;140(2):157-66. [6467607 ]
Coude MM, Charpentier C, Bonnefont JP, Cheron G, Kamoun P: Organic acids in aqueous humour and plasma: post mortem study in infants and diagnosis of enzymopathies. J Inherit Metab Dis. 1991;14(5):668-73. [1779612 ]
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 ]
Aleszczyk J: [Connection between changing the vitamin and immune status and the character of the throat microflora in patients with chronic tonsillitis]. Otolaryngol Pol. 2003;57(2):221-4. [12894427 ]
Nagarajan S, Enns GM, Millan MT, Winter S, Sarwal MM: Management of methylmalonic acidaemia by combined liver-kidney transplantation. J Inherit Metab Dis. 2005;28(4):517-24. [15902554 ]
Stabler SP, Marcell PD, Podell ER, Allen RH, Lindenbaum J: Assay of methylmalonic acid in the serum of patients with cobalamin deficiency using capillary gas chromatography-mass spectrometry. J Clin Invest. 1986 May;77(5):1606-12. [3700655 ]
Jellum E, Stokke O, Eldjarn L: Combined use of gas chromatography, mass spectrometry, and computer in diagnosis and studies of metabolic disorders. Clin Chem. 1972 Aug;18(8):800-9. [4557757 ]
Leupold D: [Methylmalonic aciduria. Classification, diagnosis and therapy (author's transl)]. Klin Wochenschr. 1977 Jan 15;55(2):57-63. [319293 ]
Vrethem M, Mattsson E, Hebelka H, Leerbeck K, Osterberg A, Landtblom AM, Balla B, Nilsson H, Hultgren M, Brattstrom L, Kagedal B: Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid. Mult Scler. 2003 Jun;9(3):239-45. [12814169 ]
Bennett MJ, Ragni MC, Hood I, Hale DE: Comparison of post-mortem urinary and vitreous humour organic acids. Ann Clin Biochem. 1992 Sep;29 ( Pt 5):541-5. [1444166 ]
Haurani FI, Hall CA, Rubin R: Megaloblastic anemia as a result of an abnormal transcobalamin II (Cardeza). J Clin Invest. 1979 Nov;64(5):1253-9. [500809 ]
Frenkel EP, Kitchens RL: Applicability of an enzymatic quantitation of methylmalonic, propionic, and acetic acids in normal and megaloblastic states. Blood. 1977 Jan;49(1):125-37. [830370 ]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Methylmalonic acid (T3D4404)

Structure for T3D4404: Methylmalonic acid