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 tricarboxylic acid cycle (aka the Citric Acid Cycle, or Krebs Cycle).^[1]

Methylmalonyl-CoA

Names
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
Identifiers
CAS Number	1264-45-5 Y
3D model (JSmol)	Interactive image
ChEBI	CHEBI:16625 N
ChemSpider	110440 N
IUPHAR/BPS	5223
PubChem CID	123909
CompTox Dashboard (EPA)	DTXSID20925529
InChI InChI=1S/C25H40N7O19P3S/c1-12(23(37)38)24(39)55-7-6-27-14(33)4-5-28-21(36)18(35)25(2,3)9-48-54(45,46)51-53(43,44)47-8-13-17(50-52(40,41)42)16(34)22(49-13)32-11-31-15-19(26)29-10-30-20(15)32/h10-13,16-18,22,34-35H,4-9H2,1-3H3,(H,27,33)(H,28,36)(H,37,38)(H,43,44)(H,45,46)(H2,26,29,30)(H2,40,41,42)/t12?,13-,16-,17-,18+,22-/m1/s1 N Key: MZFOKIKEPGUZEN-FBMOWMAESA-N N InChI=1/C25H40N7O19P3S/c1-12(23(37)38)24(39)55-7-6-27-14(33)4-5-28-21(36)18(35)25(2,3)9-48-54(45,46)51-53(43,44)47-8-13-17(50-52(40,41)42)16(34)22(49-13)32-11-31-15-19(26)29-10-30-20(15)32/h10-13,16-18,22,34-35H,4-9H2,1-3H3,(H,27,33)(H,28,36)(H,37,38)(H,43,44)(H,45,46)(H2,26,29,30)(H2,40,41,42)/t12?,13-,16-,17-,18+,22-/m1/s1 Key: MZFOKIKEPGUZEN-FBMOWMAEBZ
SMILES CC(C(=O)O)C(=O)SCCNC(=O)CCNC(=O)[C@@H](C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=NC3=C(N=CN=C32)N)O)OP(=O)(O)O)O
Properties
Chemical formula	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). N verify (what is YN ?) Infobox references

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.^[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

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.^[2] The disease is linked to Vitamin B₁₂, which is a cofactor for the enzyme 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. 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. 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.
3. Nelson DL, Cox MM (2005). Principles of Biochemistry (4th ed.). New York: W. H. Freeman. ISBN 0-7167-4339-6.
4. Kräutler B (2012). "Biochemistry of B12-cofactors in human metabolism". In Stanger O (ed.). Water Soluble Vitamins. 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.
5. 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.