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 tricarboxylic acid cycle (aka the Citric Acid Cycle, or Krebs Cycle).[1] The compound is sometimes referred to as "methylmalyl-CoA".[2]
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.[3] The latter is also formed from propionic acid, which bacteria produce in the intestine.[3] Propionyl-CoA and bicarbonate are converted to Methylmalonyl-CoA by the enzyme propionyl-CoA Carboxylase.[1] It then is converted into succinyl-CoA by methylmalonyl-CoA mutase (MUT). This reaction is a reversible isomerization. In this way, the compound enters the Citric Acid Cycle. The following diagram demonstrates the aforementioned reaction:[2]
Propionyl CoA + Bicarbonate → Methylmalonyl CoA → Succinyl CoA
Vitamin B12 plays an integral role in this reaction. Coenzyme B12 (adenosyl-cobalamin) 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.[4] The transformation of Methylmalonyl-CoA to Succinyl-CoA by this enzyme is a radical reaction.[4]
This disease occurs when methylmalonyl-CoA mutase is unable to isomerize sufficient amounts of methylmalonyl-CoA into succinyl-CoA.[5] This causes a buildup of propionic and/or methylmalonic acid, which has effects on infants ranging from severe brain damage to death.[3] The disease is linked to Vitamin B12, which is a cofactor for the enzyme methylmalonyl-CoA mutase.[5][6]
In the metabolic disease combined malonic and methylmalonic aciduria (CMAMMA), acyl-CoA synthetase family member 3 (ACSF3) is reduced, which converts toxic methylmalonic acid to methylmalonyl-CoA and thus supplies it to the citric acid cycle.[7][8] The result is an accumulation of methylmalonic acid.
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