Chemistry:Methylmalonyl-CoA
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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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3D model (JSmol)
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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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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
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]
References
- ↑ 1.0 1.1 "Propionyl-CoA carboxylase - A review". Molecular Genetics and Metabolism 122 (4): 145–152. December 2017. doi:10.1016/j.ymgme.2017.10.002. PMID 29033250.
- ↑ 2.0 2.1 2.2 "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia". Orphanet Journal of Rare Diseases 9 (1). September 2014. doi:10.1186/s13023-014-0130-8. PMID 25205257.
- ↑ Nelson, David L.; Cox, Michael M. (2005), Principles of Biochemistry (4th ed.), New York: W. H. Freeman, ISBN 0-7167-4339-6
- ↑ NIH Intramural Sequencing Center Group; Sloan, Jennifer L; Johnston, Jennifer J; Manoli, Irini; Chandler, Randy J; Krause, Caitlin; Carrillo-Carrasco, Nuria; Chandrasekaran, Suma D et al. (September 2011). "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria" (in en). Nature Genetics 43 (9): 883–886. doi:10.1038/ng.908. ISSN 1061-4036. PMID 21841779.
- ↑ 5.0 5.1 "Biochemistry of B12-cofactors in human metabolism". Water Soluble Vitamins. Subcellular Biochemistry. 56. Dordrecht: Springer Netherlands. 2012. pp. 323–346. doi:10.1007/978-94-007-2199-9_17. ISBN 978-94-007-2198-2.
- ↑ 6.0 6.1 "Role of vitamin B12 on methylmalonyl-CoA mutase activity". Journal of Zhejiang University. Science. B 13 (6): 423–437. June 2012. doi:10.1631/jzus.B1100329. PMID 22661206.
- ↑ 7.0 7.1 Head, PamelaSara E.; Myung, Sangho; Chen, Yong; Schneller, Jessica L.; Wang, Cindy; Duncan, Nicholas; Hoffman, Pauline; Chang, David et al. (2022-05-25). "Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin" (in en). Science Translational Medicine 14 (646). doi:10.1126/scitranslmed.abn4772. ISSN 1946-6234. PMID 35613279.
- ↑ "Vitamin B12 , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation". Journal of Inherited Metabolic Disease 42 (4): 673–685. July 2019. doi:10.1002/jimd.12009. PMID 30693532.
- ↑ "Considerations of expanded carrier screening: Lessons learned from combined malonic and methylmalonic aciduria". Molecular Genetics & Genomic Medicine 9 (4). April 2021. doi:10.1002/mgg3.1621. PMID 33625768.
- ↑ "Role of the malonyl-CoA synthetase ACSF3 in mitochondrial metabolism". Advances in Biological Regulation 71: 34–40. January 2019. doi:10.1016/j.jbior.2018.09.002. PMID 30201289.
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