Methylmalonyl-CoA

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 citric acid cycle.

Biosynthesis and metabolism

Methylmalonyl-CoA can be synthesized in two ways:

From propionyl-CoA: Methylmalonyl-CoA results from the metabolism of fatty acid with an odd number of carbons, of amino acids valine, isoleucine, methionine, threonine or of cholesterol side-chains, forming Propionyl-CoA. The latter is also formed from propionic acid, which bacteria produce in the intestine. Propionyl-CoA and bicarbonate are converted to Methylmalonyl-CoA by the enzyme propionyl-CoA Carboxylase. It then is converted into succinyl-CoA by methylmalonyl-CoA mutase. This reaction is a reversible isomerization. In this way, the compound enters the citric acid cycle. The following diagram demonstrates the aforementioned reaction:

Propionyl CoA + Bicarbonate → Methylmalonyl CoA → Succinyl CoA

From methylmalonic acid: The mitochondrial enzyme acyl-CoA synthetase family member 3 catalyzes the thioesterification of methylmalonic acid with coenzyme A to form methylmalonyl-CoA.

Vitamin B₁₂

Vitamin B₁₂ plays an integral role in this reaction. Coenzyme B₁₂ is an organometallic form of vitamin B₁₂ and serves as the cofactor of Methylmalonyl-CoA mutase, which is an essential enzyme in the human body. The transformation of Methylmalonyl-CoA to Succinyl-CoA by this enzyme is a radical reaction.

Related diseases

Methylmalonic Acidemia (MMA)

This disease occurs when methylmalonyl-CoA mutase is unable to isomerize sufficient amounts of methylmalonyl-CoA into succinyl-CoA. This causes a buildup of propionic and/or methylmalonic acid, which has effects on infants ranging from severe brain damage to death. However, methylmalonyl-CoA also serves as the donor for lysine methylmalonylation, a pathogenic post-translational modification proposed to play a greater role in the disease than methylmalonic acid itself. The disease is linked to vitamin B₁₂, which is a cofactor for the enzyme methylmalonyl-CoA mutase.

Combined malonic and methylmalonic aciduria (CMAMMA)

In combined malonic and methylmalonic aciduria, mutations in the ACSF3 gene impair the mitochondrial enzyme acyl-CoA synthetase family member 3, disrupting the conversion of methylmalonic acid to methylmalonyl-CoA and its entry into the citric acid cycle. This leads to accumulation of methylmalonic acid, reduced methylmalonyl-CoA levels and decreased lysine methylmalonylation compared to healthy controls.