Methylmalonic acid: Difference between revisions

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 440476652

| ImageFile=Methylmalonic acid.svg

| ImageSize=

| PIN=Methylpropanedioic acid

| OtherNames=Methylmalonic acid

|Section1={{Chembox Identifiers

| CASNo_Ref = {{cascite|correct|CAS}}

| CASNo=516-05-2

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 8LL8S712J7

| PubChem=487

| SMILES=CC(C(=O)O)C(=O)O

| ChEBI = 30860

| ChEBI_Ref = {{ebicite|changed|EBI}}

| MeSHName=Methylmalonic+acid

| EINECS = 208-219-5

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 473

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

| InChIKey = ZIYVHBGGAOATLY-UHFFFAOYAT

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

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

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = ZIYVHBGGAOATLY-UHFFFAOYSA-N

| RTECS =

| KEGG_Ref = {{keggcite|changed|kegg}}

| KEGG = C02170

|Section2={{Chembox Properties

| C=4 | H=6 | O=4

| MolarMass=118.088 g/mol

| Appearance=

| Density= 1.455 g/cm⁻³

| MeltingPtC= 134

| BoilingPt=

| Solubility=

| pKa = pK_a1 = 3,07<ref name="pKa">{{cite web|url=http://zirchrom.com/organic.htm|title=Dissociation Constants Of Organic Acids And Bases| work = ZirChrom Separations, Inc. }}</ref><br />pK_a2 = 5,76<ref name="pKa"/>

|Section3={{Chembox Hazards

| MainHazards=

| FlashPt=

| AutoignitionPt =

'''Methylmalonic acid''' ('''MMA''') ([[conjugate acid|conjugate base]] '''methylmalonate''') is a [[dicarboxylic acid]] that is a ''C''-[[Methylation|methylated]] derivative of [[malonic acid]].

== Metabolism ==

[[File:Propionate pathway.svg|left|thumb|Methylmalonic acid pathway]]

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

* [[Essential amino acid|essential amino acids]]: [[methionine]], [[valine]], [[threonine]] and [[isoleucine]]<ref name=":1">{{cite journal | vauthors = Baumgartner MR, Hörster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, Huemer M, Hochuli M, Assoun M, Ballhausen D, Burlina A, Fowler B, Grünert SC, Grünewald S, Honzik T, Merinero B, Pérez-Cerdá C, Scholl-Bürgi S, Skovby F, Wijburg F, MacDonald A, Martinelli D, Sass JO, Valayannopoulos V, Chakrapani A | display-authors = 6 | title = Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia | journal = Orphanet Journal of Rare Diseases | volume = 9 | issue = 1 | pages = 130 | date = September 2014 | pmid = 25205257 | pmc = 4180313 | doi = 10.1186/s13023-014-0130-8 | doi-access = free }}</ref>

* [[Propionic acid|propionate]] from bacterial fermentation<ref name=":1" />

* [[Odd-chain fatty acid|odd-chain fatty acids]]<ref name=":1" />

* [[cholesterol]] side chain<ref name=":1" />

[[Methylmalonyl-CoA]] – the [[coenzyme A]] linked form of methylmalonic acid – is converted into [[succinyl-CoA]] by [[methylmalonyl-CoA mutase]], in a reaction that requires [[Vitamin B12|vitamin B₁₂]] (in form of [[adenosylcobalamin]]) as a cofactor. In this way, it enters the [[Krebs cycle]], and is thus part of one of the [[anaplerotic reactions]]. In addition, the enzyme [[ACSF3]] converts methylmalonic acid back into methymalonyl-CoA.<ref>{{Cite web |title=ACSF3 gene |url=https://medlineplus.gov/genetics/gene/acsf3/ |access-date=2024-04-15 |website=Medlineplus}}</ref>

Intracellular [[Esterase|esterases]] are capable to remove the methyl group from methylmalonic acid and thus generate [[malonic acid]].<ref>{{cite journal | vauthors = McLaughlin BA, Nelson D, Silver IA, Erecinska M, Chesselet MF | title = Methylmalonate toxicity in primary neuronal cultures | journal = Neuroscience | volume = 86 | issue = 1 | pages = 279–290 | date = September 1998 | pmid = 9692761 | doi = 10.1016/S0306-4522(97)00594-0 | doi-access = free }}</ref>

==Clinical relevance==

=== Vitamin B₁₂ deficiency ===

Increased methylmalonic acid levels may indicate a vitamin [[Vitamin B12 deficiency|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).<ref>{{cite web|url=https://www.med.emory.edu/EMAC/curriculum/diagnosis/sensand.htm | archive-url = https://web.archive.org/web/20121001105756/https://www.med.emory.edu/EMAC/curriculum/diagnosis/sensand.htm | archive-date = 1 October 2012 |title=Sensitivity and Specificity| work = Emory University School of Medicine }}</ref> 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.<ref>{{cite web|url=http://www.dizziness-and-balance.com/disorders/central/b12.html|title=B12 Deficiency and Dizziness|website=www.dizziness-and-balance.com}}</ref>

=== Metabolic diseases ===

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]].<ref>{{cite journal | vauthors = de Sain-van der Velden MG, van der Ham M, Jans JJ, Visser G, Prinsen HC, Verhoeven-Duif NM, van Gassen KL, van Hasselt PM | display-authors = 6 | title = A New Approach for Fast Metabolic Diagnostics in CMAMMA | journal = JIMD Reports | volume = 30 | pages = 15–22 | date = 2016 | pmid = 26915364 | pmc = 5110436 | doi = 10.1007/8904_2016_531 | publisher = Springer Berlin Heidelberg | isbn = 978-3-662-53680-3 | veditors = Morava E, Baumgartner M, Patterson M, Rahman S | place = Berlin, Heidelberg }}</ref>

=== Cancer ===

Moreover, MMA accumulation in the blood with age has been linked with tumour progression in 2020.<ref>{{cite journal | vauthors = Gomes AP, Ilter D, Low V, Endress JE, Fernández-García J, Rosenzweig A, Schild T, Broekaert D, Ahmed A, Planque M, Elia I, Han J, Kinzig C, Mullarky E, Mutvei AP, Asara J, de Cabo R, Cantley LC, Dephoure N, Fendt SM, Blenis J | display-authors = 6 | title = Age-induced accumulation of methylmalonic acid promotes tumour progression | journal = Nature | volume = 585 | issue = 7824 | pages = 283–287 | date = September 2020 | pmid = 32814897 | pmc = 7785256 | doi = 10.1038/s41586-020-2630-0 }}</ref>

=== Bacterial overgrowth in the small intestine ===

[[Small intestinal bacterial overgrowth|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.<ref name=":0">{{cite journal | vauthors = Sentongo TA, Azzam R, Charrow J | title = Vitamin B12 status, methylmalonic acidemia, and bacterial overgrowth in short bowel syndrome | journal = Journal of Pediatric Gastroenterology and Nutrition | volume = 48 | issue = 4 | pages = 495–497 | date = April 2009 | pmid = 19322060 | doi = 10.1097/MPG.0b013e31817f9e5b | doi-access = free }}</ref><ref>{{cite journal | vauthors = Giannella RA, Broitman SA, Zamcheck N | title = Competition between bacteria and intrinsic factor for vitamin B 12 : implications for vitamin B 12 malabsorption in intestinal bacterial overgrowth | journal = Gastroenterology | volume = 62 | issue = 2 | pages = 255–260 | date = February 1972 | pmid = 4629318 | doi = 10.1016/s0016-5085(72)80177-x }}</ref> It has been shown that in these cases, methylmalonic acid levels returned to normal with the administration of [[metronidazole]].<ref name=":0" /><ref>{{cite journal | vauthors = Jimenez L, Stamm DA, Depaula B, Duggan CP | title = Is Serum Methylmalonic Acid a Reliable Biomarker of Vitamin B12 Status in Children with Short Bowel Syndrome: A Case Series | journal = The Journal of Pediatrics | volume = 192 | pages = 259–261 | date = January 2018 | pmid = 29129351 | pmc = 6029886 | doi = 10.1016/j.jpeds.2017.09.024 }}</ref>

== Measurement ==

MMA concentrations in blood are measured by [[Gas-liquid chromatography|gas chromatographic]] [[mass spectrometry]] or [[Liquid chromatography–mass spectrometry|LC-MS]] and the expected values of MMA in healthy people are between 73 and 271 nmol/L.<ref>{{Cite thesis | url=http://scidok.sulb.uni-saarland.de/volltexte/2007/1076/pdf/Thesis.pdf | doi=10.22028/D291-20838| year=2007| vauthors = Isber S | title=The role of poor nutritional status and hyperhomocysteinemia in complicated pregnancy in Syria| type=doctoralThesis}}</ref><ref>{{cite web|url=http://ltd.aruplab.com/Tests/Pub/0099431|title=Methylmalonic Acid, Serum or Plasma (Vitamin B12&nbsp;Status)|website=ltd.aruplab.com}}</ref>

== See also ==

== References ==

== Further reading ==

* [https://www.ncbi.nlm.nih.gov/pubmed/21947532 Vitamin B12, cognition, and brain MRI measures: a cross-sectional examination.]

[[Category:Dicarboxylic acids]]