Chemistry:Malonyl-CoA

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Malonyl-CoA is a coenzyme A derivative of malonic acid.

Biosynthesis

Malonyl-CoA cannot freely cross membranes and there is no known malonyl-CoA import mechanism.[1][2] The biosynthesis therefore takes place locally:

Functions

It plays a key role in fatty acid biosynthesis and polyketide biosynthesis, fatty acid elongation, fatty acid oxidation via CPT1, the mTOR signaling pathway, and lysine malonylation.

Fatty acid synthesis and elongation

Cytosolic malonyl-CoA, derived from ACC1, serves as the two-carbon donor for cytosolic fatty acid synthesis by fatty acid synthase (FAS I), which is most active in lipogenic tissues such as the liver, adipose tissue, and the lactating mammary gland, and to a lesser extent in the kidney, brain and lung.[7][8] The malonyl group from malonyl-CoA is transferred to the acyl carrier protein (ACP) domain of FAS I by its malonyl/acetyltransferase (MAT) domain, releasing CoA.[9] The β-ketoacyl synthase (KS) domain then catalyzes condensation of malonyl-ACP with the KS-bound growing acyl chain, extending it by two carbons per cycle.[9] In the liver and adipose tissue, fatty acid synthesis produces palmitate (C16:0), the precursor for membrane and storage lipids as well as for protein palmitoylation.[10] In contrast, the human mammary gland mainly synthesizes medium chain fatty acids (MCFAs; C6–C12) for milk-fat production.[11]

Cytosolic malonyl-CoA also provides the two-carbon donor for fatty acid elongation on the cytosolic side of the smooth endoplasmic reticulum (ER).[12][13] The chemistry is analogous to cytosolic fatty acid synthesis but is carried out by four separate membrane-bound enzymes and uses CoA instead of ACP as the carrier.[14] Fatty acids originating from cytosolic fatty acid synthesis or dietary uptake are first activated to acyl-CoAs by acyl-CoA synthetases and subsequently elongated by ELOVL enzymes through condensation with ACC1-derived malonyl-CoA, extending the acyl chain by two carbons per cycle.[15] Depending on the specific ELOVL enzyme (ELOVL1–7) and its substrate specificity, fatty acid elongation produces distinct long-chain fatty acids (LCFAs; C12–C20) and very long chain fatty acids (VLCFAs; >C20) that serve as precursors of membrane phospholipids, sphingolipids, and signaling lipids.[12][16] Highly expressed ELOVL enzymes are found in skin (ELOVL1), brain (ELOVL2), liver (ELOVL2, ELOVL6), brown adipose tissue (ELOVL3), retina (ELOVL4), testis and epididymis (ELOVL5), adipose tissue (ELOVL6), pancreas, kidney, prostate, and colon (ELOVL7).[16]

File:Mitochondrial fatty acid synthesis (mtFAS) pathway.svg
Overview of the mitochondrial fatty acid synthesis (mtFAS) pathway, which uses malonyl-CoA as the two-carbon donor.

Mitochondrial malonyl-CoA serves as the two-carbon donor in mitochondrial fatty acid synthesis (mtFAS), similar to cytosolic fatty acid synthesis.[17] This pathway, however, uses identical chemistry but relies on separate, monofunctional enzymes (FAS II) rather than a single multifunctional complex (FAS I).[18] mtFAS is located in the mitochondrial matrix and is present in nearly all tissues, showing particularly high activity in energy-demanding tissues such as the heart, skeletal muscle, brain, and nervous system.[19][20] In each cycle, malonyl-CoA:ACP transferase (MCAT) transfers the malonyl group from malonyl-CoA to mitochondrial acyl carrier protein (mtACP), and β-ketoacyl synthase (OXSM) condenses the resulting malonyl-mtACP with the mtACP-bound acyl chain, extending it by two carbons.[19] Through successive cycles, this generates octanoyl-mtACP (C8:0), a precursor for protein lipoylation essential for the catalytic activity of mitochondrial multienzyme complexes including pyruvate dehydrogenase complex, α-ketoglutarate dehydrogenase complex, branched-chain α-keto acid dehydrogenase complex, the glycine cleavage system, and the 2-oxoadipate dehydrogenase complex.[19] In addition, mtFAS produces longer acyl-mtACP species that allosterically activate a network of LYRM proteins required for iron–sulfur cluster biogenesis, assembly of electron transport chain complexes, and function of the electron-transfer flavoprotein.[21]

Inhibitor

Beyond its biosynthetic role as a two-carbon donor in fatty acid synthesis and elongation, malonyl-CoA also serves as an inhibitor of enzymes:[22][23]

Cytosolic malonyl-CoA, derived from ACC2, allosterically inhibits carnitine palmitoyltransferase I (CPT1), the rate-limiting enzyme on the outer mitochondrial membrane that catalyzes the association of long-chain fatty acids with carnitine, thereby preventing their transport into mitochondria.[22] Within mitochondria, these fatty acids undergo β-oxidation to generate acetyl-CoA and the reducing equivalents NADH and FADH2, providing a major energy source in oxidative tissues such as heart (~60%), skeletal muscle, and kidney, or supplying acetyl-CoA for ketone body synthesis in the liver during prolonged fasting.[24][25] CPT1 sensitivity to malonyl-CoA varies by isoform and tissue, with CPT1B – predominant in oxidative tissues such as skeletal muscle and heart – showing greater sensitivity to malonyl-CoA inhibition than CPT1A, which is mainly expressed in liver and other lipogenic tissues.[25] By inhibiting CPT1, malonyl-CoA prevents a futile cycle of simultaneous fatty acid synthesis and degradation.[1]

Cytosolic malonyl-CoA also binds to the catalytic pocket of mTOR, acting as an ATP-competitive inhibitor that suppresses mTORC1 kinase activity.[23] This interaction provides a metabolic feedback link between cytosolic fatty acid synthesis and mTORC1 signaling, allowing cells to coordinate their growth and biosynthetic activity with lipid availability.[23]

Lysine malonylation

Main article: Biology:Lysine malonylation
File:Malonyllysine.svg
Protein with a malonylated lysine residue at physiological pH. The malonyl group (in red) originates from malonyl-CoA.

Malonyl-CoA serves as the donor for lysine malonylation, a reversible post-translational modification (PTM) that occurs particularly in mitochondria, but also in the cytosol and nucleus.[26] It involves the covalent attachment of a malonyl group to the ε-amino group of lysine residues in proteins.[27] This reverses the side chain’s charge from +1 to −1 and adds greater bulk, thereby altering protein structure, interactions, and function.[28][29] Lysine malonylation depends directly on the availability of malonyl-CoA, thereby linking the metabolic state to protein regulation.[30] Altered lysine malonylation is associated with angiogenesis, cancer, histone modification, immune regulation, obesity, osteoarthritis, and type 2 diabetes, among others.[31]

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 serves as an intermediate in the mitochondrial clearance of toxic malonate, a potent inhibitor of succinate dehydrogenase (Complex II).[6] Defects in the enzymes of this pathway cause the metabolic disorders combined malonic and methylmalonic aciduria (CMAMMA) and malonic aciduria.[6] In CMAMMA (prevalence: 1: 30,000), the malonyl-CoA synthetase ACSF3 (encoded by ACSF3) is defective, impairing the ligation of malonate to CoA and leading to malonate accumulation and respiratory inhibition.[32][6] Reported symptoms include neurological and metabolic manifestations such as seizures, cognitive decline, developmental delay, ketoacidosis, and hypoglycemia.[32] In malonic aciduria (prevalence: <1: 1,000,000), malonyl-CoA decarboxylase (encoded by MLYCD) is defective, preventing decarboxylation of malonyl-CoA to acetyl-CoA, resulting in its accumulation and inhibition of fatty acid oxidation.[33][6] Reported features include developmental delay, seizure disorders, hypoglycemia, and cardiomyopathy.[6]

Malonate+CoA+ATP →ACSF3Malonyl−CoA Synthetase Malonyl−CoA →MLYCDMalonyl−CoA Decarboxylase Acetyl−CoA

References

  1. ↑ 1.0 1.1 Bowman, Caitlyn E.; Rodriguez, Susana; Selen Alpergin, Ebru S.; Acoba, Michelle G.; Zhao, Liang; Hartung, Thomas; Claypool, Steven M.; Watkins, Paul A. et al. (2017). "The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency" (in en). Cell Chemical Biology 24 (6): 673–684.e4. doi:10.1016/j.chembiol.2017.04.009. PMID 28479296. 
  2. ↑ 2.0 2.1 Nowinski, Sara M.; Van Vranken, Jonathan G.; Dove, Katja K.; Rutter, Jared (October 2018). "Impact of Mitochondrial Fatty Acid Synthesis on Mitochondrial Biogenesis" (in en). Current Biology 28 (20): R1212–R1219. doi:10.1016/j.cub.2018.08.022. PMID 30352195. Bibcode: 2018CBio...28R1212N. 
  3. ↑ Lehninger principles of biochemistry (5th ed.). 2008. p. 806. 
  4. ↑ 4.0 4.1 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" (in en). Biochemical Journal 474 (22): 3783–3797. doi:10.1042/BCJ20170416. ISSN 0264-6021. PMID 28986507. https://portlandpress.com/biochemj/article/474/22/3783/49536/A-conserved-mammalian-mitochondrial-isoform-of. 
  5. ↑ 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. PMID 21846720. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 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. PMID 30201289. 
  7. ↑ Wakil, Salih J.; Abu-Elheiga, Lutfi A. (April 2009). "Fatty acid metabolism: target for metabolic syndrome". Journal of Lipid Research 50 (Suppl): S138–S143. doi:10.1194/jlr.r800079-jlr200. ISSN 0022-2275. PMID 19047759. Bibcode: 2009JLipR..50S.138W. 
  8. ↑ Kumari, Asha (2023). "Fatty acid biosynthesis" (in en). Sweet Biochemistry. Elsevier BV. pp. 31–36. doi:10.1016/b978-0-443-15348-8.00031-4. ISBN 978-0-443-15348-8. https://linkinghub.elsevier.com/retrieve/pii/B9780443153488000314. 
  9. ↑ 9.0 9.1 Rittner, Alexander; Paithankar, Karthik S.; Himmler, Aaron; Grininger, Martin (February 2020). "Type I fatty acid synthase trapped in the octanoyl-bound state" (in en). Protein Science 29 (2): 589–605. doi:10.1002/pro.3797. ISSN 0961-8368. PMID 31811668. 
  10. ↑ Carta, Gianfranca; Murru, Elisabetta; Banni, Sebastiano; Manca, Claudia (2017-11-08). "Palmitic Acid: Physiological Role, Metabolism and Nutritional Implications". Frontiers in Physiology 8. doi:10.3389/fphys.2017.00902. ISSN 1664-042X. PMID 29167646. 
  11. ↑ Mohammad, Mahmoud A.; Sunehag, Agneta L.; Haymond, Morey W. (2014-04-01). "De novo synthesis of milk triglycerides in humans" (in en). American Journal of Physiology. Endocrinology and Metabolism 306 (7): E838–E847. doi:10.1152/ajpendo.00605.2013. ISSN 0193-1849. PMID 24496312. 
  12. ↑ 12.0 12.1 Nie, Laiyin; Pascoa, Tomas C.; Pike, Ashley C. W.; Bushell, Simon R.; Quigley, Andrew; Ruda, Gian Filippo; Chu, Amy; Cole, Victoria et al. (June 2021). "The structural basis of fatty acid elongation by the ELOVL elongases" (in en). Nature Structural & Molecular Biology 28 (6): 512–520. doi:10.1038/s41594-021-00605-6. ISSN 1545-9993. PMID 34117479. 
  13. ↑ Jump, Donald B. (2009). "Mammalian fatty acid elongases". Lipidomics. Methods in Molecular Biology (Clifton, N.J.). 579. pp. 375–389. doi:10.1007/978-1-60761-322-0_19. ISBN 978-1-60761-321-3. 
  14. ↑ Jakobsson, A; Westerberg, R; Jacobsson, A (May 2006). "Fatty acid elongases in mammals: Their regulation and roles in metabolism" (in en). Progress in Lipid Research 45 (3): 237–249. doi:10.1016/j.plipres.2006.01.004. PMID 16564093. https://linkinghub.elsevier.com/retrieve/pii/S0163782706000051. 
  15. ↑ Kihara, A. (2012-11-01). "Very long-chain fatty acids: elongation, physiology and related disorders" (in en). Journal of Biochemistry 152 (5): 387–395. doi:10.1093/jb/mvs105. ISSN 0021-924X. PMID 22984005. https://academic.oup.com/jb/article-lookup/doi/10.1093/jb/mvs105. 
  16. ↑ 16.0 16.1 Wang, Xiangyu; Yu, Hao; Gao, Rong; Liu, Ming; Xie, Wenli (2023-11-20). "A comprehensive review of the family of very-long-chain fatty acid elongases: structure, function, and implications in physiology and pathology" (in en). European Journal of Medical Research 28 (1). doi:10.1186/s40001-023-01523-7. ISSN 2047-783X. PMID 37981715. 
  17. ↑ Guan, Xin (2014). Enzymatic components and physiological roles of mitochondrial fatty acid biosynthesis in plants (Doctor of Philosophy thesis). Ames: Iowa State University, Digital Repository. doi:10.31274/etd-180810-137.
  18. ↑ Wedan, Riley J.; Longenecker, Jacob Z.; Nowinski, Sara M. (January 2024). "Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism" (in en). Cell Metabolism 36 (1): 36–47. doi:10.1016/j.cmet.2023.11.017. PMID 38128528. 
  19. ↑ 19.0 19.1 19.2 Nowinski, Sara M; Solmonson, Ashley; Rusin, Scott F; Maschek, J Alan; Bensard, Claire L; Fogarty, Sarah; Jeong, Mi-Young; Lettlova, Sandra et al. (2020-08-17). "Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria" (in en). eLife 9. doi:10.7554/eLife.58041. ISSN 2050-084X. PMID 32804083. 
  20. ↑ Nair, Remya R.; Koivisto, Henna; Jokivarsi, Kimmo; Miinalainen, Ilkka J.; Autio, Kaija J.; Manninen, Aki; Poutiainen, Pekka; Tanila, Heikki et al. (2018-11-07). "Impaired Mitochondrial Fatty Acid Synthesis Leads to Neurodegeneration in Mice" (in en). The Journal of Neuroscience 38 (45): 9781–9800. doi:10.1523/JNEUROSCI.3514-17.2018. ISSN 0270-6474. PMID 30266742. 
  21. ↑ Masud, Ali J.; Kastaniotis, Alexander J.; Rahman, M. Tanvir; Autio, Kaija J.; Hiltunen, J. Kalervo (December 2019). "Mitochondrial acyl carrier protein (ACP) at the interface of metabolic state sensing and mitochondrial function" (in en). Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1866 (12). doi:10.1016/j.bbamcr.2019.118540. PMID 31473256. 
  22. ↑ 22.0 22.1 Ma, Yibao; Temkin, Sarah M.; Hawkridge, Adam M.; Guo, Chunqing; Wang, Wei; Wang, Xiang-Yang; Fang, Xianjun (October 2018). "Fatty acid oxidation: An emerging facet of metabolic transformation in cancer" (in en). Cancer Letters 435: 92–100. doi:10.1016/j.canlet.2018.08.006. PMID 30102953. Bibcode: 2018CancL.435...92M. 
  23. ↑ 23.0 23.1 23.2 Nicastro, Raffaele; Brohée, Laura; Alba, Josephine; Nüchel, Julian; Figlia, Gianluca; Kipschull, Stefanie; Gollwitzer, Peter; Romero-Pozuelo, Jesus et al. (September 2023). "Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor" (in en). Nature Cell Biology 25 (9): 1303–1318. doi:10.1038/s41556-023-01198-6. ISSN 1465-7392. PMID 37563253. 
  24. ↑ Talley, Jacob T.; Mohiuddin, Shamim S. (2025), "Biochemistry, Fatty Acid Oxidation", StatPearls (Treasure Island (FL): StatPearls Publishing), PMID 32310462, http://www.ncbi.nlm.nih.gov/books/NBK556002/, retrieved 2025-11-12 
  25. ↑ 25.0 25.1 van Weeghel, Michel; Abdurrachim, Desiree; Nederlof, Rianne; Argmann, Carmen A; Houtkooper, Riekelt H; Hagen, Jacob; Nabben, Miranda; Denis, Simone et al. (2018-08-01). "Increased cardiac fatty acid oxidation in a mouse model with decreased malonyl-CoA sensitivity of CPT1B" (in en). Cardiovascular Research 114 (10): 1324–1334. doi:10.1093/cvr/cvy089. ISSN 0008-6363. PMID 29635338. https://academic.oup.com/cardiovascres/article/114/10/1324/4964875. 
  26. ↑ Colak, Gozde; Pougovkina, Olga; Dai, Lunzhi; Tan, Minjia; te Brinke, Heleen; Huang, He; Cheng, Zhongyi; Park, Jeongsoon et al. (November 2015). "Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation" (in en). Molecular & Cellular Proteomics 14 (11): 3056–3071. doi:10.1074/mcp.M115.048850. PMID 26320211. 
  27. ↑ Peng, Chao; Lu, Zhike; Xie, Zhongyu; Cheng, Zhongyi; Chen, Yue; Tan, Minjia; Luo, Hao; Zhang, Yi et al. (December 2011). "The First Identification of Lysine Malonylation Substrates and Its Regulatory Enzyme" (in en). Molecular & Cellular Proteomics 10 (12). doi:10.1074/mcp.M111.012658. PMID 21908771. 
  28. ↑ Hirschey, Matthew D.; Zhao, Yingming (September 2015). "Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation" (in en). Molecular & Cellular Proteomics 14 (9): 2308–2315. doi:10.1074/mcp.R114.046664. PMID 25717114. 
  29. ↑ Xu, Yan; Ding, Ya-Xin; Ding, Jun; Wu, Ling-Yun; Xue, Yu (2016-12-02). "Mal-Lys: prediction of lysine malonylation sites in proteins integrated sequence-based features with mRMR feature selection". Scientific Reports 6. doi:10.1038/srep38318. ISSN 2045-2322. PMID 27910954. Bibcode: 2016NatSR...638318X. 
  30. ↑ Du, Yipeng; Cai, Tanxi; Li, Tingting; Xue, Peng; Zhou, Bo; He, Xiaolong; Wei, Peng; Liu, Pingsheng et al. (January 2015). "Lysine malonylation is elevated in type 2 diabetic mouse models and enriched in metabolic associated proteins". Molecular & Cellular Proteomics 14 (1): 227–236. doi:10.1074/mcp.M114.041947. ISSN 1535-9484. PMID 25418362. 
  31. ↑ Zou, Lu; Yang, Yanyan; Wang, Zhibin; Fu, Xiuxiu; He, Xiangqin; Song, Jiayi; Li, Tianxiang; Ma, Huibo et al. (2023-02-01). "Lysine Malonylation and Its Links to Metabolism and Diseases". Aging and Disease 14 (1): 84–98. doi:10.14336/AD.2022.0711. ISSN 2152-5250. PMID 36818560. 
  32. ↑ 32.0 32.1 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. 
  33. ↑ "Orphanet: Malonic aciduria" (in en). https://www.orpha.net/en/disease/detail/943. 



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