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]

Biosynthesis and metabolism

Methylmalonyl-CoA pathway

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

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]

Related diseases

Methylmalonic Acidemia (MMA)

Main article: Methylmalonyl-CoA mutase deficiency

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 the metabolic precursor to methylmalonyl-CoA mutase.[5][6]

Combined malonic and methylmalonic aciduria (CMAMMA)

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.

References

  1. ^ a b Wongkittichote P, Ah Mew N, Chapman KA (December 2017). "Propionyl-CoA carboxylase - A review". Molecular Genetics and Metabolism. 122 (4): 145–152. doi:10.1016/j.ymgme.2017.10.002. PMC 5725275. PMID 29033250.
  2. ^ a b Nelson DL, Cox MM (2005). Principles of Biochemistry (4th ed.). New York: W. H. Freeman. ISBN 0-7167-4339-6.
  3. ^ a b c Baumgartner MR, Hörster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, et al. (September 2014). "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia". Orphanet Journal of Rare Diseases. 9 (1): 130. doi:10.1186/s13023-014-0130-8. PMC 4180313. PMID 25205257.
  4. ^ a b Kräutler B (2012). Stanger O (ed.). Biochemistry of B12-cofactors in human metabolism. Subcellular Biochemistry. Vol. 56. Dordrecht: Springer Netherlands. pp. 323–346. doi:10.1007/978-94-007-2199-9_17. ISBN 978-94-007-2198-2. PMID 22116707. {{cite book}}: |work= ignored (help)
  5. ^ a b Takahashi-Iñiguez T, García-Hernandez E, Arreguín-Espinosa R, Flores ME (June 2012). "Role of vitamin B12 on methylmalonyl-CoA mutase activity". Journal of Zhejiang University. Science. B. 13 (6): 423–437. doi:10.1631/jzus.B1100329. PMC 3370288. PMID 22661206.
  6. ^ Froese DS, Fowler B, Baumgartner MR (July 2019). "Vitamin B12 , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation". Journal of Inherited Metabolic Disease. 42 (4): 673–685. doi:10.1002/jimd.12009. PMID 30693532.
  7. ^ Gabriel MC, Rice SM, Sloan JL, Mossayebi MH, Venditti CP, Al-Kouatly HB (April 2021). "Considerations of expanded carrier screening: Lessons learned from combined malonic and methylmalonic aciduria". Molecular Genetics & Genomic Medicine. 9 (4): e1621. doi:10.1002/mgg3.1621. PMC 8123733. PMID 33625768.
  8. ^ Bowman CE, Wolfgang MJ (January 2019). "Role of the malonyl-CoA synthetase ACSF3 in mitochondrial metabolism". Advances in Biological Regulation. 71: 34–40. doi:10.1016/j.jbior.2018.09.002. PMC 6347522. PMID 30201289.