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), also known as malonyl-CoA synthetase or malonate:CoA ligase (AMP-forming), is an enzyme that catalyzes the chemical reaction:
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.
Representatives of the malonate—CoA ligase family are required for malonate detoxification, mitochondrial fatty acid synthesis, lysine malonylation, and acetyl-CoA synthesis.[1][2]
Examples
The following enzymes with malonyl-CoA synthetase activity are known:
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, in addition to malonate, also accepts methylmalonate as a substrate with approximately 70% efficiency.[3] ACSF3 is required for the clearance of intramitochondrial malonate, as malonate is a potent inhibitor of mitochondrial respiration through the competitive inhibition of succinate dehydrogenase (Complex II), an enzyme that simultaneously functions in the citric acid cycle and the respiratory chain.[1][4] In addition to the mitochondrial isoform of acetyl-CoA carboxylase 1 (mtACC1), which produces malonyl-CoA from acetyl-CoA, ACSF3 hereby contributes to the mitochondrial malonyl-CoA pool required for mitochondrial fatty acid synthesis, lysine malonylation, acetyl-CoA synthesis, and incorporation into cellular lipids.[5][2][1]
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).[6] Malonyl-CoA is required as a substrate in acylation and condensation reactions.[7] 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.[7] In contrast, the mitochondrial isoform is essential for plant growth.[7]
Clinical relevance
In the inborn error of metabolism combined malonic and methylmalonic aciduria (CMAMMA), the malonyl-CoA synthetase ACSF3 is defective, leading to an accumulation of malonate and methylmalonate, and to a deficiency of malonyl-CoA and methylmalonyl-CoA.[8]
References
- ^ a b c Bowman CE, Rodriguez S, Selen Alpergin ES, Acoba MG, Zhao L, Hartung T, et al. (June 2017). "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. PMC 5482780. PMID 28479296.
- ^ a b Wehbe Z, Behringer S, Alatibi K, Watkins D, Rosenblatt D, Spiekerkoetter U, et al. (November 2019). "The emerging role of the mitochondrial fatty-acid synthase (mtFASII) in the regulation of energy metabolism". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1864 (11): 1629–1643. doi:10.1016/j.bbalip.2019.07.012. PMID 31376476.
- ^ Witkowski A, Thweatt J, Smith S (September 2011). "Mammalian ACSF3 protein is a malonyl-CoA synthetase that supplies the chain extender units for mitochondrial fatty acid synthesis". The Journal of Biological Chemistry. 286 (39): 33729–33736. doi:10.1074/jbc.M111.291591. PMC 3190830. PMID 21846720.
- ^ 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.
- ^ Monteuuis G, Suomi F, Kerätär JM, Masud AJ, Kastaniotis AJ (November 2017). "A conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with ACSF3". The Biochemical Journal. 474 (22): 3783–3797. doi:10.1042/BCJ20170416. PMID 28986507.
- ^ Chen H, Kim HU, Weng H, Browse J (June 2011). "Malonyl-CoA synthetase, encoded by ACYL ACTIVATING ENZYME13, is essential for growth and development of Arabidopsis". The Plant Cell. 23 (6): 2247–2262. Bibcode:2011PlanC..23.2247C. doi:10.1105/tpc.111.086140. PMC 3160029. PMID 21642549.
- ^ a b c Guan X, Nikolau BJ (March 2016). "AAE13 encodes a dual-localized malonyl-CoA synthetase that is crucial for mitochondrial fatty acid biosynthesis". The Plant Journal. 85 (5): 581–593. Bibcode:2016PlJ....85..581G. doi:10.1111/tpj.13130. PMID 26836315.
- ^ Head PE, Myung S, Chen Y, Schneller JL, Wang C, Duncan N, et al. (May 2022). "Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin". Science Translational Medicine. 14 (646) eabn4772. doi:10.1126/scitranslmed.abn4772. PMC 10468269. PMID 35613279.