Methylmalonic acid

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Methylmalonic acid
Names
Preferred IUPAC name
Methylpropanedioic acid
Other names
Methylmalonic acid
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.007.473 Edit this at Wikidata
EC Number
  • 208-219-5
KEGG
MeSH Methylmalonic+acid
UNII
  • InChI=1S/C4H6O4/c1-2(3(5)6)4(7)8/h2H,1H3,(H,5,6)(H,7,8) ☒N
    Key: ZIYVHBGGAOATLY-UHFFFAOYSA-N ☒N
  • InChI=1/C4H6O4/c1-2(3(5)6)4(7)8/h2H,1H3,(H,5,6)(H,7,8)
    Key: ZIYVHBGGAOATLY-UHFFFAOYAT
  • CC(C(=O)O)C(=O)O
Properties
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[1]
pKa2 = 5,76[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Methylmalonic acid (MMA) (conjugate base methylmalonate) is a dicarboxylic acid that is a C-methylated derivative of malonic acid.

Metabolism

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, it enters the Krebs cycle, and is thus part of one of the anaplerotic reactions.

Methylmalonic acid is a by-product of certain metabolic processes. The sources of this include the following:

Intracellular esterases are capable to remove the methyl group from methylmalonic acid and thus generate malonic acid.[3]

Clinical relevance

Vitamin B12 deficiency

Increased methylmalonic acid levels may indicate a vitamin B12 deficiency. However, it is sensitive (those with the deficiency almost always test positive) but not specific (those that do not have vitamin B12 deficiency may have elevated levels of methylmalonic acid detected).[4] MMA is elevated in 90–98% of patients with B12 deficiency. It has lower specificity as 20–25% of patients over the age of 70 have elevated levels of MMA, but 25–33% of them do not have B12 deficiency. For this reason, MMA test is not routinely recommended in the elderly.[5]

Metabolic diseases

An excess is associated with methylmalonic acidemia.

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 plasma, CMAMMA can be distinguished from classic methylmalonic acidemia.[6]

Cancer

Moreover, MMA accumulation in the blood with age has been linked with tumour progression in 2020.[7]

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. 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 propionate, which is a precursor to methylmalonic acid.[8][9] It has been shown that in these cases, methylmalonic acid levels returned to normal with the administration of metronidazole.[8][10]

Measurement

MMA concentrations in blood are measured by gas chromatographic mass spectrometry or LC-MS and the expected values of MMA in healthy people are between 73 and 271 nmol/L.[11][12]

See also

References

  1. ^ a b "Dissociation Constants Of Organic Acids And Bases". ZirChrom Separations, Inc.
  2. ^ a b c d 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.
  3. ^ 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.
  4. ^ "Sensitivity and Specificity". Emory University School of Medicine. Archived from the original on 1 October 2012.
  5. ^ "B12 Deficiency and Dizziness". www.dizziness-and-balance.com.
  6. ^ 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.
  7. ^ 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.
  8. ^ a b Sentongo TA, Azzam R, Charrow J (April 2009). "Vitamin B12 status, methylmalonic acidemia, and bacterial overgrowth in short bowel syndrome". Journal of Pediatric Gastroenterology and Nutrition. 48 (4): 495–497. doi:10.1097/MPG.0b013e31817f9e5b. PMID 19322060.
  9. ^ 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.
  10. ^ 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.
  11. ^ Isber S (2007). The role of poor nutritional status and hyperhomocysteinemia in complicated pregnancy in Syria (PDF) (doctoralThesis). doi:10.22028/D291-20838.
  12. ^ "Methylmalonic Acid, Serum or Plasma (Vitamin B12 Status)". ltd.aruplab.com.

Further reading