Methylmalonyl-CoA
Chemical compound
From Wikipedia, the free encyclopedia
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.[1]
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| Systematic IUPAC name
(9R)-1-[(2R,3S,4R,5R)-5-(6-Amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)oxolan-2-yl]-3,5,9-trihydroxy-8,8,20-trimethyl-3,5,10,14,19-pentaoxo-2,4,6-trioxa-18-thia-11,15-diaza-3λ5,5λ5-diphosphahenicosan-21-oic acid | |
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CompTox Dashboard (EPA) |
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| Properties | |
| C25H40N7O19P3S | |
| Molar mass | 867.608 g/mol |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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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.[2] The latter is also formed from propionic acid, which bacteria produce in the intestine.[2] 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:[3]
Propionyl CoA + Bicarbonate → Methylmalonyl CoA → Succinyl CoA
- From methylmalonic acid: The mitochondrial enzyme acyl-CoA synthetase family member 3 (ACSF3) catalyzes the thioesterification of methylmalonic acid with coenzyme A (CoA) to form methylmalonyl-CoA.[4]
Vitamin B12
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.[5] The transformation of Methylmalonyl-CoA to Succinyl-CoA by this enzyme is a radical reaction.[5]
Related diseases
Methylmalonic Acidemia (MMA)
This disease occurs when methylmalonyl-CoA mutase is unable to isomerize sufficient amounts of methylmalonyl-CoA into succinyl-CoA.[6] This causes a buildup of propionic and/or methylmalonic acid, which has effects on infants ranging from severe brain damage to death.[2] 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.[7] The disease is linked to vitamin B12, which is a cofactor for the enzyme methylmalonyl-CoA mutase.[6][8]
Combined malonic and methylmalonic aciduria (CMAMMA)
In combined malonic and methylmalonic aciduria (CMAMMA), mutations in the ACSF3 gene impair the mitochondrial enzyme acyl-CoA synthetase family member 3 (ACSF3), disrupting the conversion of methylmalonic acid to methylmalonyl-CoA and its entry into the citric acid cycle.[9][10] This leads to accumulation of methylmalonic acid, reduced methylmalonyl-CoA levels and decreased lysine methylmalonylation compared to healthy controls.[7]
