Malonate—CoA ligase
| Malonate—CoA ligase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 6.2.1.76 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| |||||||||
In enzymology, a malonate—CoA ligase (EC 6.2.1.76) is an enzyme that catalyzes the chemical reaction:
- ATP + malonate + CoA AMP + diphosphate + malonyl-CoA
The 3 substrates of this enzyme are ATP, malonate, and CoA, whereas its 3 products are AMP, diphosphate, and malonyl-CoA.
This enzyme belongs to the class of ligases, specifically those forming carbon-sulfur bonds as acid-thiol ligases or, more precisely, to the family of acyl-CoA synthetases. The systematic name of this enzyme class is malonate:CoA ligase (AMP-forming). This enzyme is also called malonyl-CoA synthetase. This enzyme participates in mitochondrial fatty acid synthesis metabolism.
Examples
Examples of enzymes with malonyl-CoA synthetase activity are:
Acyl-CoA synthetase family member 3 (ACSF3)
The only known malonyl-CoA synthetase in mammals is the mitochondrial enzyme acyl-CoA synthetase family member 3 (ACSF3), which has a high specificity for malonate and methylmalonate.[1] ACSF3 is required for the detoxification of intramitochondrial malonate, as malonate is a potent inhibitor of mitochondrial respiration through the competitive inhibition of succinate dehydrogenase, which is a component of citric acid cycle and is complex II of the respiratory chain.[2][3] The resulting malonyl-CoA (besides being generated by a mitochondrial isoform of acetyl-CoA carboxylase) is considered one of the sources of mitochondrial malonyl-CoA, which is required as a precursor for mitochondrial fatty acid synthesis.[4] Furthermore, ACSF3 is required for the malonylation of mitochondrial proteins.[2]
Acyl activating enzyme 13 (AAE13)
Also in plants, more precisely in Arabidopsis thaliana, there is a malonyl-CoA synthetase, the acyl activation enzyme 13 (AAE13).[5] Malonyl-CoA is required as a substrate in acylation and condensation reactions.[6] AAE13 is localized both in the cytosol and in the mitochondria, whereby the cytosolic isoform is not essential, as cytosolic malonyl-CoA is sufficiently provided by cytosolic acetyl-CoA carboxylase.[6] In contrast, the mitochondrial isoform is essential for plant growth.[6]
Clinical relevance
In the inborn error of metabolism combined malonic and methylmalonic aciduria (CMAMMA), the malonyl-CoA synthetase, ACSF3, is impaired, which leads to an accumulation of the metabolites malonate and methylmalonate.[7]
References
- ^ Witkowski, Andrzej; Thweatt, Jennifer; Smith, Stuart (September 2011). "Mammalian ACSF3 Protein Is a Malonyl-CoA Synthetase That Supplies the Chain Extender Units for Mitochondrial Fatty Acid Synthesis". Journal of Biological Chemistry. 286 (39): 33729–33736. doi:10.1074/jbc.M111.291591. PMC 3190830. PMID 21846720.
- ^ a b Bowman, Caitlyn E.; Rodriguez, Susana; Alpergin, Ebru S. Selen; Acoba, Michelle G.; Zhao, Liang; Hartung, Thomas; Claypool, Steven M.; Watkins, Paul A.; Wolfgang, Michael J. (2017-06-22). "The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency". Cell Chemical Biology. 24 (6): 673–684.e4. doi:10.1016/j.chembiol.2017.04.009. ISSN 2451-9456. PMC 5482780. PMID 28479296.
- ^ Bowman, Caitlyn E.; Wolfgang, Michael J. (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.
- ^ Monteuuis, Geoffray; Suomi, Fumi; Kerätär, Juha M.; Masud, Ali J.; Kastaniotis, Alexander J. (2017-11-15). "A conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with ACSF3". Biochemical Journal. 474 (22): 3783–3797. doi:10.1042/BCJ20170416. ISSN 0264-6021. PMID 28986507.
- ^ Chen, Hui; Kim, Hyun Uk; Weng, Hua; Browse, John (2011-06-01). "Malonyl-CoA Synthetase, Encoded by ACYL ACTIVATING ENZYME13 , Is Essential for Growth and Development of Arabidopsis". The Plant Cell. 23 (6): 2247–2262. doi:10.1105/tpc.111.086140. ISSN 1532-298X. PMC 3160029. PMID 21642549.
- ^ a b c Guan, Xin; Nikolau, Basil J. (March 2016). "AAE 13 encodes a dual-localized malonyl-CoA synthetase that is crucial for mitochondrial fatty acid biosynthesis". The Plant Journal. 85 (5): 581–593. doi:10.1111/tpj.13130. ISSN 0960-7412. PMID 26836315.
- ^ de Sain-van der Velden, Monique G. M.; van der Ham, Maria; Jans, Judith J.; Visser, Gepke; Prinsen, Hubertus C. M. T.; Verhoeven-Duif, Nanda M.; van Gassen, Koen L. I.; van Hasselt, Peter M. (2016), Morava, Eva; Baumgartner, Matthias; Patterson, Marc; Rahman, Shamima (eds.), "A New Approach for Fast Metabolic Diagnostics in CMAMMA", JIMD Reports, Volume 30, vol. 30, Berlin, Heidelberg: Springer Berlin Heidelberg, pp. 15–22, doi:10.1007/8904_2016_531, ISBN 978-3-662-53680-3, PMC 5110436, PMID 26915364
