Methylmalonic acid

Methylmalonic acid
Names
	Preferred IUPAC name Methylpropanedioic acid
	Other names Methylmalonic acid
Identifiers
CAS Number	516-05-2 ;
3D model (JSmol)	Interactive image ;
ChEBI	CHEBI:30860 ;
ChemSpider	473 ;
ECHA InfoCard	100.007.473
EC Number	208-219-5;
KEGG	C02170 ;
MeSH	Methylmalonic+acid
PubChem CID	487 ;
UNII	8LL8S712J7 ;
CompTox Dashboard (EPA)	DTXSID00199549 ;
	InChI InChI=1S/C4H6O4/c1-2(3(5)6)4(7)8/h2H,1H3,(H,5,6)(H,7,8) Key: ZIYVHBGGAOATLY-UHFFFAOYSA-N ; InChI=1/C4H6O4/c1-2(3(5)6)4(7)8/h2H,1H3,(H,5,6)(H,7,8) Key: ZIYVHBGGAOATLY-UHFFFAOYAT;
	SMILES CC(C(=O)O)C(=O)O;
Properties
Chemical formula	C4H6O4
Molar mass	118.088 g/mol
Density	1.455 g/cm−3
Melting point	134 °C (273 °F; 407 K)
Acidity (pKa)	pKa1 = 3,07; pKa2 = 5,76
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). verify (what is ?) Infobox references

Last updated October 13, 2024

Methylmalonic acid (MMA) is a chemical compound from the group of dicarboxylic acids. It consists of the basic structure of malonic acid and also carries a methyl group. The salts of methylmalonic acid are called methylmalonates.

Metabolism

Methylmalonic acid is a by-product of the propionate metabolism pathway.^[2] The starting sources for this are the following with the respective approximate contributions to whole body propionate metabolism in brackets:^[3]

essential amino acids: methionine, valine, threonine and isoleucine ^[4] (~ 50%)^[3]
odd-chain fatty acids ^[4] (~ 30%)^[3]
propionic acid from bacterial fermentation^[4] (~ 20%)^[3]
cholesterol side chain^[4]
thymine ^[5]

The propionate derivative, propionyl-CoA, is converted into D-methylmalonyl-CoA by propionyl-CoA carboxylase and then converted into L-methylmalonyl-CoA by methylmalonyl-CoA epimerase.^[6] Entry into the citric acid cycle occurs through the conversion of L-methylmalonyl-CoA into succinyl-CoA by L-methylmalonyl-CoA mutase, whereby vitamin B₁₂ in the form of adenosylcobalamin is required as a coenzyme.^[2] This degradation pathway from propionyl-CoA to succinyl-CoA represents one of the most important anaplerotic pathways of the citric acid cycle.^[7] Methylmalonic acid is formed as a by-product of this metabolic pathway when D-methylmalonyl-CoA is cleaved into methylmalonic acid and CoA by D-methylmalonyl-CoA hydrolase.^[5]^[2] The enzyme acyl-CoA synthetase family member 3 (ACSF3) is in turn responsible for the conversion of methylmalonic acid and CoA to methylmalonyl-CoA.^[8]

Intracellular esterases are capable to remove the methyl group (-CH₃) from methylmalonic acid and thus generate malonic acid.^[9]

Clinical relevance

Vitamin B₁₂ deficiency

Increased methylmalonic acid levels may indicate a vitamin B₁₂ deficiency. The test is highly sensitive (those with vitamin B₁₂ deficiency almost always have raised levels) but not very specific (those that do not have vitamin B₁₂ deficiency may have raised levels too).^[10] Methylmalonic acid is elevated in 90–98% of patients with vitamin B₁₂ deficiency. It has lower specificity since 20–25% of patients over the age of 70 have elevated levels of methylmalonic acid, but 25–33% of them do not have B₁₂ deficiency. For this reason, the testing of methylmalonic acid levels is not routinely recommended in the elderly.^[11]

Metabolic diseases

An excess is associated with methylmalonic acidemias.

If elevated methylmalonic acid levels are accompanied by elevated malonic acid levels, this may indicate the metabolic disease combined malonic and methylmalonic aciduria (CMAMMA). By calculating the malonic acid to methylmalonic acid ratio in blood plasma, CMAMMA can be distinguished from classic methylmalonic acidemia.^[12]

Cancer

Moreover, methylmalonic acid accumulation in the blood with age has been linked with tumour progression in 2020.^[13]

Bacterial overgrowth in the small intestine

Bacterial overgrowth in the small intestine can also lead to elevated levels of methylmalonic acid due to the competition of bacteria in the absorption process of vitamin B₁₂.^[14]^[15] This is true of vitamin B₁₂ from food and oral supplementation and can be circumvented by vitamin B₁₂ injections. It is also hypothesized from case studies of patients with short bowel syndrome that intestinal bacterial overgrowth leads to increased production of propionic acid, which is a precursor to methylmalonic acid.^[16] It has been shown that in these cases, methylmalonic acid levels returned to normal with the administration of metronidazole.^[16]^[17]

Measurement

Methylmalonic acid concentrations in blood are measured by gas chromatographic mass spectrometry or liquid chromatography–mass spectrometry (LC-MS) and the expected values of methylmalonic acid in healthy people are between 73 and 271 nmol/L.^[18]^[19]

Related Research Articles

Threonine is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group, a carboxyl group, and a side chain containing a hydroxyl group, making it a polar, uncharged amino acid. It is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Threonine is synthesized from aspartate in bacteria such as E. coli. It is encoded by all the codons starting AC.

Propionic acid is a naturally occurring carboxylic acid with chemical formula CH^₃CH^₂CO^₂H. It is a liquid with a pungent and unpleasant smell somewhat resembling body odor. The anion CH^₃CH^₂CO⁻
₂ as well as the salts and esters of propionic acid are known as propionates or propanoates.

Methylmalonic acidemias, also called methylmalonic acidurias, are a group of inherited metabolic disorders, that prevent the body from properly breaking down proteins and fats. This leads to a buildup of a toxic level of methylmalonic acid in body liquids and tissues. Due to the disturbed branched-chain amino acids (BCAA) metabolism, they are among the classical organic acidemias.

Propionic acidemia, also known as propionic aciduria or propionyl-CoA carboxylase deficiency, is a rare autosomal recessive metabolic disorder, classified as a branched-chain organic acidemia.

Succinyl-coenzyme A, abbreviated as succinyl-CoA or SucCoA, is a thioester of succinic acid and coenzyme A.

Small intestinal bacterial overgrowth (SIBO), also termed bacterial overgrowth, or small bowel bacterial overgrowth syndrome (SBBOS), is a disorder of excessive bacterial growth in the small intestine. Unlike the colon, which is rich with bacteria, the small bowel usually has fewer than 100,000 organisms per millilitre. Patients with bacterial overgrowth typically develop symptoms which may include nausea, bloating, vomiting, diarrhea, malnutrition, weight loss, and malabsorption by various mechanisms.

<span class="mw-page-title-main">Malonyl-CoA</span> Chemical compound

Malonyl-CoA is a coenzyme A derivative of malonic acid.

Calcium propanoate or calcium propionate has the formula Ca(C₂H₅COO)₂. It is the calcium salt of propanoic acid.

<span class="mw-page-title-main">Malonic aciduria</span> Medical condition

Malonic aciduria or malonyl-CoA decarboxylase deficiency (MCD) is an autosomal-recessive metabolic disorder caused by a genetic mutation that disrupts the activity of Malonyl-CoA decarboxylase. This enzyme breaks down Malonyl-CoA into acetyl-CoA and carbon dioxide.

Methylmalonyl-CoA mutase is a mitochondrial homodimer apoenzyme that focuses on the catalysis of methylmalonyl CoA to succinyl CoA. The enzyme is bound to adenosylcobalamin, a hormonal derivative of vitamin B12 in order to function. Methylmalonyl-CoA mutase deficiency is caused by genetic defect in the MUT gene responsible for encoding the enzyme. Deficiency in this enzyme accounts for 60% of the cases of methylmalonic acidemia.

Methylmalonyl-CoA mutase (EC 5.4.99.2, MCM), mitochondrial, also known as methylmalonyl-CoA isomerase, is a protein that in humans is encoded by the MUT gene. This vitamin B₁₂-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA in humans. Mutations in MUT gene may lead to various types of methylmalonic aciduria.

Propionyl-CoA is a coenzyme A derivative of propionic acid. It is composed of a 24 total carbon chain and its production and metabolic fate depend on which organism it is present in. Several different pathways can lead to its production, such as through the catabolism of specific amino acids or the oxidation of odd-chain fatty acids. It later can be broken down by propionyl-CoA carboxylase or through the methylcitrate cycle. In different organisms, however, propionyl-CoA can be sequestered into controlled regions, to alleviate its potential toxicity through accumulation. Genetic deficiencies regarding the production and breakdown of propionyl-CoA also have great clinical and human significance.

<span class="mw-page-title-main">Propionyl-CoA carboxylase</span>

Propionyl-CoA carboxylase (EC 6.4.1.3, PCC) catalyses the carboxylation reaction of propionyl-CoA in the mitochondrial matrix. PCC has been classified both as a ligase and a lyase. The enzyme is biotin-dependent. The product of the reaction is (S)-methylmalonyl CoA.

<span class="mw-page-title-main">Hydroxocobalamin</span> Form of vitamin B12

Hydroxocobalamin, also known as vitamin B_12a and hydroxycobalamin, is a vitamin found in food and used as a dietary supplement. As a supplement it is used to treat vitamin B12 deficiency including pernicious anemia. Other uses include treatment for cyanide poisoning, Leber's optic atrophy, and toxic amblyopia. It is given by injection into a muscle or vein, by pill or sublingually.

<span class="mw-page-title-main">Methylmalonyl-CoA</span> Chemical compound

Methylmalonyl-CoA is the thioester consisting of coenzyme A linked to methylmalonic acid. It is an important intermediate in the biosynthesis of succinyl-CoA, which plays an essential role in the tricarboxylic acid cycle.

Methylmalonyl CoA epimerase is an enzyme involved in fatty acid catabolism that is encoded in human by the "MCEE" gene located on chromosome 2. It is routinely and incorrectly labeled as "methylmalonyl-CoA racemase". It is not a racemase because the CoA moiety has 5 other stereocenters.

<span class="mw-page-title-main">Cyanocobalamin</span> Form of vitamin B-12

Cyanocobalamin is a form of vitamin B^₁₂ used to treat and prevent vitamin B^₁₂ deficiency except in the presence of cyanide toxicity. The deficiency may occur in pernicious anemia, following surgical removal of the stomach, with fish tapeworm, or due to bowel cancer. It is used by mouth, by injection into a muscle, or as a nasal spray.

Methylmalonate-semialdehyde dehydrogenase [acylating], mitochondrial (MMSDH) is an enzyme that in humans is encoded by the ALDH6A1 gene.

Combined malonic and methylmalonic aciduria (CMAMMA), also called combined malonic and methylmalonic acidemia is an inherited metabolic disease characterized by elevated levels of malonic acid and methylmalonic acid. However, the methylmalonic acid levels exceed those of malonic acid. CMAMMA is not only an organic aciduria but also a defect of mitochondrial fatty acid synthesis (mtFASII). Some researchers have hypothesized that CMAMMA might be one of the most common forms of methylmalonic acidemia, and possibly one of the most common inborn errors of metabolism. Due to being infrequently diagnosed, it most often goes undetected.

References

1 2 "Dissociation Constants Of Organic Acids And Bases". ZirChrom Separations, Inc.
1 2 3 Tejero, Joanne; Lazure, Felicia; Gomes, Ana P. (March 2024). "Methylmalonic acid in aging and disease". Trends in Endocrinology & Metabolism. 35 (3): 188–200. doi:10.1016/j.tem.2023.11.001. ISSN 1043-2760. PMC 10939937 . PMID 38030482.
1 2 3 4 Chandler, R.J.; Venditti, C.P. (September 2005). "Genetic and genomic systems to study methylmalonic acidemia". Molecular Genetics and Metabolism. 86 (1–2): 34–43. doi:10.1016/j.ymgme.2005.07.020. PMC 2657357 . PMID 16182581.
1 2 3 4 Baumgartner MR, Hörster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, et al. (September 2014). "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia". Orphanet Journal of Rare Diseases. 9 (1): 130. doi: 10.1186/s13023-014-0130-8 . PMC 4180313 . PMID 25205257.
1 2 Kovachy, Robin J.; Stabler, Sally P.; Allen, Robert H. (1988), "[49] d-methylmalonyl-CoA hydrolase", Methods in Enzymology, vol. 166, Elsevier, pp. 393–400, doi:10.1016/s0076-6879(88)66051-4, ISBN 978-0-12-182067-1, PMID 3071714
↑ Diogo, Rui; Rua, Inês B; Ferreira, Sara; Nogueira, Célia; Pereira, Cristina; Rosmaninho-Salgado, Joana; Diogo, Luísa (2023-10-31). "Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features". Cureus. 15 (10). doi: 10.7759/cureus.48017 . ISSN 2168-8184. PMC 10687495 . PMID 38034150.
↑ Collado, M. Sol; Armstrong, Allison J.; Olson, Matthew; Hoang, Stephen A.; Day, Nathan; Summar, Marshall; Chapman, Kimberly A.; Reardon, John; Figler, Robert A.; Wamhoff, Brian R. (July 2020). "Biochemical and anaplerotic applications of in vitro models of propionic acidemia and methylmalonic acidemia using patient-derived primary hepatocytes". Molecular Genetics and Metabolism. 130 (3): 183–196. doi:10.1016/j.ymgme.2020.05.003. PMC 7337260 . PMID 32451238.
↑ "ACSF3 gene". Medlineplus. Retrieved 2024-04-15.
↑ McLaughlin BA, Nelson D, Silver IA, Erecinska M, Chesselet MF (September 1998). "Methylmalonate toxicity in primary neuronal cultures". Neuroscience. 86 (1): 279–290. doi: 10.1016/S0306-4522(97)00594-0 . PMID 9692761.
↑ "Sensitivity and Specificity". Emory University School of Medicine. Archived from the original on 1 October 2012.
↑ "B12 Deficiency and Dizziness". www.dizziness-and-balance.com.
↑ de Sain-van der Velden MG, van der Ham M, Jans JJ, Visser G, Prinsen HC, Verhoeven-Duif NM, et al. (2016). Morava E, Baumgartner M, Patterson M, Rahman S (eds.). "A New Approach for Fast Metabolic Diagnostics in CMAMMA". JIMD Reports. 30. Berlin, Heidelberg: Springer Berlin Heidelberg: 15–22. doi:10.1007/8904_2016_531. ISBN 978-3-662-53680-3. PMC 5110436 . PMID 26915364.
↑ Gomes AP, Ilter D, Low V, Endress JE, Fernández-García J, Rosenzweig A, et al. (September 2020). "Age-induced accumulation of methylmalonic acid promotes tumour progression". Nature. 585 (7824): 283–287. doi:10.1038/s41586-020-2630-0. PMC 7785256 . PMID 32814897.
↑ Dukowicz, Andrew C.; Lacy, Brian E.; Levine, Gary M. (February 2007). "Small Intestinal Bacterial Overgrowth". Gastroenterology & Hepatology. 3 (2): 112–122. ISSN 1554-7914. PMC 3099351 . PMID 21960820.
↑ Giannella RA, Broitman SA, Zamcheck N (February 1972). "Competition between bacteria and intrinsic factor for vitamin B 12 : implications for vitamin B 12 malabsorption in intestinal bacterial overgrowth". Gastroenterology. 62 (2): 255–260. doi:10.1016/s0016-5085(72)80177-x. PMID 4629318.
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↑ Jimenez L, Stamm DA, Depaula B, Duggan CP (January 2018). "Is Serum Methylmalonic Acid a Reliable Biomarker of Vitamin B12 Status in Children with Short Bowel Syndrome: A Case Series". The Journal of Pediatrics. 192: 259–261. doi:10.1016/j.jpeds.2017.09.024. PMC 6029886 . PMID 29129351.
↑ Isber S (2007). The role of poor nutritional status and hyperhomocysteinemia in complicated pregnancy in Syria (PDF) (doctoralThesis). doi:10.22028/D291-20838.
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Methylmalonic acid

Contents

Metabolism