Methylmalonic acid (MMA) (

conjugate base A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...

methylmalonate) is a dicarboxylic acid that is a ''C''- methylated derivative of malonate. The

coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...

linked form of methylmalonic acid, methylmalonyl-CoA, is converted into

succinyl-CoA Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A. Sources It is an important intermediate in the citric acid cycle, where it is synthesized from α-ketoglutarate by α-ketoglutarate de ...

by methylmalonyl-CoA mutase, in a reaction that requires vitamin B₁₂ as a cofactor. In this way, it enters the

Krebs cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...

, and is thus part of one of the

anaplerotic reactions Anaplerotic reactions, a term coined by Hans Kornberg and originating from the Greeἀνά 'up' anπληρόω 'to fill', are chemical reactions that form intermediates of a metabolic pathway. Examples of such are found in the citric acid cycle (TC ...

Pathology

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). 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. Moreover, recently MMA accumulation in the blood with age had been linked with tumour progression. Bacterial overgrowth in the

small intestine The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through t ...

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. It has been shown that in these cases, methylmalonic acid levels returned to normal with the administration of

metronidazole Metronidazole, sold under the brand name Flagyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vaginosis. It is e ...

. 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. MMA concentrations in blood are measured by gas chromatographic

mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a '' mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is u ...

or LC-MS and the expected values of MMA in healthy people are between 73 and 271 nmol/L.{{cite web, url=http://ltd.aruplab.com/Tests/Pub/0099431, title=Methylmalonic Acid, Serum or Plasma (Vitamin B12 Status), website=ltd.aruplab.com

Pathology

See also

References

Further reading