Malonyl-CoA is a coenzyme A derivative of malonic acid.
Biosynthesis
Malonyl-CoA cannot cross membranes and there is no known malonyl-CoA import mechanism.[1][2] The biosynthesis therefore takes place locally:
- cytosol: Malonyl-CoA is formed by carboxylating acetyl-CoA using the highly regulated enzyme acetyl-CoA carboxylase 1 (ACC1). One molecule of acetyl-CoA joins with a molecule of bicarbonate,[3] requiring energy rendered from ATP.
- mitochondrial outer membran: Malonyl-CoA is formed by carboxylating acetyl-CoA using the highly regulated enzyme acetyl-CoA carboxylase 2 (ACC2). The reaction is the same as with ACC1.
- mitochondrial matrix: Malonyl-CoA is formed in coordinated fashion by mtACC1, a mitochondrial isoform of ACC1, and acyl-CoA synthetase family member 3 (ACSF3), a mitochondrial malonyl-CoA synthetase.[4] MtACC1, like cytosolic ACC1 catalyses the carboxylation of acetyl-CoA, while ACSF3 catalyses the thioesterification of malonate to coenzyme A.[5][4] The latter serves for the clearance of mitochondrial malonate, since malonate is a potent inhibitor of mitochondrial respiration as it competitively inhibits succinate dehydrogenase.[6] However, the source of malonyl-CoA in the mitochondria is still up for debate.[2]
Functions
It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis.
Cytosolic malonyl-CoA
Malonyl-CoA provides 2-carbon units to fatty acids and commits them to fatty acid chain synthesis.
Malonyl-CoA is utilised in fatty acid biosynthesis by the enzyme malonyl coenzyme A:acyl carrier protein transacylase (MCAT). MCAT serves to transfer malonate from malonyl-CoA to the terminal thiol of holo-acyl carrier protein (ACP).
Malonyl-CoA is a highly regulated molecule in fatty acid synthesis; as such, it inhibits the rate-limiting step in beta-oxidation of fatty acids.[6] Malonyl-CoA inhibits fatty acids from associating with carnitine by regulating the enzyme carnitine palmitoyltransferase, thereby preventing them from entering the mitochondria, where fatty acid oxidation and degradation occur.
Polyketide biosynthesis
MCAT is also involved in bacterial polyketide biosynthesis. The enzyme MCAT together with an acyl carrier protein (ACP), and a polyketide synthase (PKS) and chain-length factor heterodimer, constitutes the minimal PKS of type II polyketides.
Clinical relevance
Malonyl-CoA plays a special role in the mitochondrial clearance of toxic malonic acid in the metabolic disorders combined malonic and methylmalonic aciduria (CMAMMA) and malonic aciduria.[6] In CMAMMA, malonyl-CoA synthetase, ACSF3 is impaired, which generates mitochondrial malonyl-CoA from malonic acid, which can then be converted to acetyl-CoA by malonyl-CoA decarboxylase.[5][6] In contrast, in malonic aciduria, malonyl-CoA decarboxylase is decreased, which converts malonyl-CoA to acetyl-CoA.[6]
![{\displaystyle \mathrm {Malonic\ acid+CoA+ATP\ {\xrightarrow[{ACSF3}]{Malonyl{-}CoA\ Synthetase}}\ Malonyl{-}CoA\ {\xrightarrow[{MLYCD}]{Malonyl-CoA\ Decarboxylase}}\ Acetyl{-}CoA} }](https://wikimedia.org/api/rest_v1/media/math/render/svg/f3389fec9ec81ec307389ddc12b767a2fd82069f)
See also
References
- ^ Bowman, Caitlyn E.; Rodriguez, Susana; Selen Alpergin, Ebru S.; Acoba, Michelle G.; Zhao, Liang; Hartung, Thomas; Claypool, Steven M.; Watkins, Paul A.; Wolfgang, Michael J. (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 Nowinski, Sara M.; Van Vranken, Jonathan G.; Dove, Katja K.; Rutter, Jared (October 2018). "Impact of Mitochondrial Fatty Acid Synthesis on Mitochondrial Biogenesis". Current Biology. 28 (20): R1212 – R1219. Bibcode:2018CBio...28R1212N. doi:10.1016/j.cub.2018.08.022. PMC 6258005. PMID 30352195.
- ^ Nelson D, Cox M (2008). Lehninger principles of biochemistry (5th ed.). p. 806.
- ^ a b 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.
- ^ a b 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. ISSN 0021-9258. PMC 3190830. PMID 21846720.
- ^ a b c d e 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.
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