Methylmalonyl-CoA

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

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]

Biosynthesis and metabolism

Propionate metabolic pathway with L- and D-methylmalonyl-CoA as intermediates.

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 thioester ification 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)

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. ^[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]

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. NIH Intramural Sequencing Center Group; Sloan, Jennifer L; Johnston, Jennifer J; Manoli, Irini; Chandler, Randy J; Krause, Caitlin; Carrillo-Carrasco, Nuria; Chandrasekaran, Suma D; Sysol, Justin R; O'Brien, Kevin; Hauser, Natalie S; Sapp, Julie C; Dorward, Heidi M; Huizing, Marjan; Barshop, Bruce A (September 2011). "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria". Nature Genetics. 43 (9): 883–886. doi:10.1038/ng.908. ISSN   1061-4036. PMC   3163731 . PMID   21841779.
5. 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.
6. 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.
7. Head, PamelaSara E.; Myung, Sangho; Chen, Yong; Schneller, Jessica L.; Wang, Cindy; Duncan, Nicholas; Hoffman, Pauline; Chang, David; Gebremariam, Abigael; Gucek, Marjan; Manoli, Irini; Venditti, Charles P. (2022-05-25). "Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin". Science Translational Medicine. 14 (646). doi:10.1126/scitranslmed.abn4772. ISSN   1946-6234. PMC   10468269 . PMID   35613279.
8. 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.
9. 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.
10. 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.