Methylmalonic acid structure, properties, synthesis, uses

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Simon Doyle
Methylmalonic acid structure, properties, synthesis, uses

The methylmalonic acid is an organic compound whose chemical formula is C4H6OR4 or HOOC-CH (CH3) -COOH. It is a dicarboxylic acid also known as 2-methylpropanedioic acid. It is found in the human body as it is a derivative of metabolism.

Methylmalonic acid is an intermediate in the metabolism of fats and proteins. Its transformation within the body towards another compound depends on the presence of an enzyme derived from cobalamin or vitamin B12.

Human cell visualized through a fluorescence microscope. In its cytoplasm, methylmalonic acid is formed. Bluish green: core. Red: Membrane. Marc Vidal [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]. Source: Wikimedia Commons.

When its concentration in the blood serum reaches high values, problems such as vitamin B12 deficiency or genetic deficiency of some enzymes are suspected. For this reason, its most relevant use is for the determination of vitamin B12 deficiency..

High levels of methylmalonic acid can cause problems with the nervous system and kidneys. If the levels are excessively high, a metabolic disorder called aciduria occurs, for which a curative drug has not been found, since it has only been controlled to a certain extent.

However, medical scientists are studying new ways to treat aciduria caused by methylmalonic acid..

Article index

  • 1 Structure
  • 2 Nomenclature
  • 3 Properties
    • 3.1 Physical state
    • 3.2 Molecular weight
    • 3.3 Melting point
    • 3.4 Solubility
    • 3.5 Dissociation constant
  • 4 Location in nature
    • 4.1 Training in the human body
    • 4.2 Normal amount of MMA in human blood serum
    • 4.3 Disease associated with high levels of methylmalonic acid
  • 5 Synthesis
  • 6 Use as a biomarker for vitamin B12 or cobalamin deficiency
  • 7 References

Structure

Methylmalonic acid is formed by a main chain of 3 carbons of which the one in the center has a methyl group attached to it -CH3 and the end carbons belong to -COOH groups. Therefore it is a dicarboxylic acid.

Malonic acid or 2-methylpropanedioic acid molecule structure. Fvasconcellos 18:59, 26 May 2007 (UTC) [Public domain]. Source: Wikimedia Commons.

Nomenclature

- Methylmalonic acid

- 2-methylpropanedioic acid

- 1,1-ethanedicarboxylic acid

- MMA MethylMalonic Acid)

Properties

Physical state

Solid.

Molecular weight

118.09 g / mol

Melting point

135 ºC

Solubility

In water: 679.0 mg / mL

Dissociation constant

pKto = 3.12 (at 20 ºC)

Location in nature

It is a human metabolite. That means it is formed during certain metabolic processes, especially from fats and proteins. It was isolated from human urine for the first time in 1957. It is located mainly in the cellular cytoplasm of the kidneys and liver..

Its concentration above normal values ​​is associated with many diseases, such as vitamin B12 deficiency or cobalamin malabsorption, deficiency of some enzymes such as mutase, fumarase, among others, which can be caused by genetic defects.

The early detection of a negative balance of cobalamin in the organism is carried out by determining the increase of methylmalonic acid in serum. In other words, when vitamin B12 is deficient, the concentration of MMA in serum increases..

MMA interferes with energy production in the mitochondria by inhibiting succinate dehydrogenase, an electron transporting protein complex.

Mitochondrion, a place in the cell where malonic acid can interfere with normal metabolic processes. Louisa Howard [Public domain]. Source: Wikimedia Commons.

Consequently, a high MMA can have a negative effect on health. Its negative effect on the nervous system and kidneys has been reported. On the other hand, a very large excess of MMA causes aciduria.

Training in the human body

MMA is found in the body as part of the coenzyme L-methylmalonyl-CoA. When there is a malfunction of the enzyme L-methylmalonyl-CoA-mutase, MMA is formed.

The enzyme L-methylmalonyl-CoA-mutase requires adenosyl-cobalamin, a coenzyme of vitamin B-12, which catalyzes the reversible isomerization of L-methylmalonyl-CoA to succinyl-CoA. Therefore, when there is not enough adenosyl-cobalamin, excess MMA is obtained..

Normal amount of MMA in human blood serum

According to studies carried out in the USA, the race or ethnicity of the person affects the normal content of MMA in the blood serum.

Blood analysis laboratory. Author: Darko Stojanovic. Source: Pixabay.

Non-Hispanic whites have a significantly higher serum MMA concentration than Hispanic-Mexicans and non-Hispanic Afro-descendants, the latter having the lowest serum MMA concentration. The age of the person was also found to influence the level of MMA.

MMA concentration begins to increase after age 40 and continues to increase with age. After age 70 it increases sharply.

The latter could be attributed to impaired kidney function. However, it is not clear whether excess MMA damages the kidneys or whether damage to the kidneys for other reasons causes an increase in MMA..

Disease associated with high levels of methylmalonic acid

Very high levels of MMA cause a metabolic disorder called MMA aciduria or acidemia..

It is promoted by a partial or total deficiency of the enzyme methylmalonyl-CoA-mutase, which is a mitochondrial enzyme dependent on vitamin B12, which intervenes in the final step of the oxidation of valine, isoleucine and fatty acids.

There are no approved therapies for this disease. Its management is reduced to the reduction of protein intake, carnitine and cofactor supplementation and medical monitoring.

However, a possible therapy has been developed that consists of intravenous administration of messenger RNA encapsulated in biodegradable lipid nanoparticles..

Author: frolicsomepl. Source: Pixabay.

Said messenger RNA encodes the formation of the enzyme methylmalonyl-CoA-mutase, which leads to the reduction of MMA in plasma.

Synthesis

One of the syntheses of methylmalonic acid in the laboratory that has attracted attention is the reaction of potassium acrylate with potassium tetracarbonylhydruroferrate for 4 hours at 70 ºC under an atmosphere of carbon monoxide CO.

The reaction is catalytic and highly reproducible, where mild conditions and a yield greater than 95% stand out. It was the first hydrocarboxylation of acrylic acid to give MMA.

Use as a biomarker for vitamin B12 or cobalamin deficiency

High levels of MMA in blood serum have been associated with vitamin B12 deficiency. It is estimated that the concentration of MMA increases in the serum before the decrease in cobalamin is detected in the serum or causes damage to the body.

In studies of vegans and lacto-ovovegetarians, serum MMA has been used to determine vitamin B12 deficiency.

Human blood tests. Source: Pixabay.

Certain investigators found that metformin treatment of patients with type 2 diabetes is associated with increased serum MMA concentration. This effect increases with the time of treatment with metformin and is associated with the decrease of vitamin B12 levels in these patients..

In addition, MMA has been tested to determine vitamin B12 deficiency in patients with cancerous tumors and also in pregnant women..

However, other researchers suggest that the usefulness of serum MMA concentration in determining vitamin B12 deficiency is limited in patients with normal kidney function and in very young people..

References

  1. U.S. National Library of Medicine. (2019). Methylmalonic acid. Recovered from: pubchem.ncbi.nlm.nih.gov.
  2. Ganji, V. and Kafai, M.R. (2018). Population Reference Values ​​for Serum Methylmalonic Acid Concentrations and Its Relationship with Age, Sex, Race-Ethnicity, Supplement Use, Kidney Function and Serum Vitamin B12 in the Post-Folic Acid Fortification. Nutrients 2018, 10 (1): 74. Recovered from ncbi.nlm.nih.gov.
  3. Gallego-Narbón, A. et al. (2018). Methylmalonic Acid Levels and their Relation with Cobalamin Supplementation in Spanish Vegetarians. Plant Foods for Human Nutrition 2018, 73 (3): 166-171. Recovered from ncbi.nlm.nih.gov.
  4. Out, M. et al. (2018). Long-term treatment with metformin in type 2 diabetes and methylmalonic acid: Post Hoc Analysis of a randomized controlled 4.3 year trial. Journal of Diabetes and its Complications. Volume 32, Issue 2, February 2018, Pages 171-178. Recovered from sciencedirect.com.
  5. An, D. et al. (2017). Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia. Cell Reports 2017, 21 (12), 3548-3558. Recovered from sciencedirect.com.
  6. Vashi, P. et al. (2016). Methylmalonic Acid and Homocysteine ​​as Indicators of Vitamin B-12 Deficiency in Cancer. PLoS ONE 2016 11 (1): e0147843. Recovered from ncbi.nlm.nih.gov.
  7. Choi, R. et al. (2016). A Prospective Study on Serum Methylmalonic and Homocysteine ​​in Pregnant Women. Nutrients 2016, 8 (12): 797. Recovered from ncbi.nlm.nih.gov.
  8. Brunet, J.-J. and Passelaigue, E. (1990). Fully Regioselective Catalytic Carbonylation of Acrylic Derivatives: Synthesis of Methylmalonic Acid by Iron Pentacarbonyl Catalyzed Hydrocarboxylation of Acrylic Acid. Organometallics 1990, 9, 1711-1713. Recovered from pubs.acs.org.

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