Malonyl-CoA

Last updated
Malonyl-CoA
Malonyl-CoA2.svg
Names
Preferred 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-3,5,10,14,19-pentaoxo-8,8-dimethyl-2,4,6-trioxa-18-thia-11,15-diaza-3λ5,5λ5-diphosphahenicosan-21-oic acid
Identifiers
ChemSpider
ECHA InfoCard 100.007.596 OOjs UI icon edit-ltr-progressive.svg
MeSH Malonyl+CoA
PubChem CID
UNII
  • InChI=1S/C24H38N7O19P3S/c1-24(2,19(37)22(38)27-4-3-13(32)26-5-6-54-15(35)7-14(33)34)9-47-53(44,45)50-52(42,43)46-8-12-18(49-51(39,40)41)17(36)23(48-12)31-11-30-16-20(25)28-10-29-21(16)31/h10-12,17-19,23,36-37H,3-9H2,1-2H3,(H,26,32)(H,27,38)(H,33,34)(H,42,43)(H,44,45)(H2,25,28,29)(H2,39,40,41)/t12-,17-,18-,19+,23-/m1/s1 Yes check.svgY
    Key: LTYOQGRJFJAKNA-DVVLENMVSA-N Yes check.svgY
Properties
C24H38N7O19P3S
Molar mass 853.582
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

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

Contents

Biosynthesis

Malonyl-CoA cannot 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]

Overview of the mitochondrial fatty acid synthesis (mtFAS) pathway, which uses malonyl-CoA as the two-carbon donor. 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 the soluble mitochondrial acyl carrier protein (mtACP), and β-ketoacyl synthase (OXSM) condenses the resulting malonyl-ACP with the mtACP-bound acyl chain, extending it by two carbons. [19] Through successive cycles, this generates octanoyl-ACP (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-ACP species that allosterically activate a network of LYRM proteins required for mitochondrial translation, iron–sulfur cluster biogenesis, and assembly of electron transport chain complexes. [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

Protein with a malonylated lysine residue at physiological pH. Malonyl-CoA donates the malonyl group (in red) for this post-translational modification. Malonyllysine.svg
Protein with a malonylated lysine residue at physiological pH. Malonyl-CoA donates the malonyl group (in red) for this post-translational modification.

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]

References

  1. 1 2 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.
  2. 1 2 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.
  3. ↑ Nelson D, Cox M (2008). Lehninger principles of biochemistry (5th ed.). p. 806.
  4. 1 2 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.
  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. PMC   3190830 . PMID   21846720.
  6. 1 2 3 4 5 6 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.
  7. ↑ Wakil, Salih J.; Abu-Elheiga, Lutfi A. (April 2009). "Fatty acid metabolism: target for metabolic syndrome". Journal of Lipid Research. 50: S138 –S143. doi: 10.1194/jlr.r800079-jlr200 . ISSN   0022-2275. PMC   2674721 . PMID   19047759.
  8. ↑ Kumari, Asha (2023). Fatty acid biosynthesis. Elsevier BV. pp. 31–36. doi:10.1016/b978-0-443-15348-8.00031-4. ISBN   978-0-443-15348-8.
  9. 1 2 Rittner, Alexander; Paithankar, Karthik S.; Himmler, Aaron; Grininger, Martin (February 2020). "Type I fatty acid synthase trapped in the octanoyl‐bound state". Protein Science. 29 (2): 589–605. doi: 10.1002/pro.3797 . ISSN   0961-8368. PMC   6954729 . 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. PMC   5682332 . PMID   29167646.
  11. ↑ Mohammad, Mahmoud A.; Sunehag, Agneta L.; Haymond, Morey W. (2014-04-01). "De novo synthesis of milk triglycerides in humans". American Journal of Physiology-Endocrinology and Metabolism. 306 (7): E838 –E847. doi:10.1152/ajpendo.00605.2013. ISSN   0193-1849. PMC   3962611 . PMID   24496312.
  12. 1 2 Nie, Laiyin; Pascoa, Tomas C.; Pike, Ashley C. W.; Bushell, Simon R.; Quigley, Andrew; Ruda, Gian Filippo; Chu, Amy; Cole, Victoria; Speedman, David; Moreira, Tiago; Shrestha, Leela; Mukhopadhyay, Shubhashish M. M.; Burgess-Brown, Nicola A.; Love, James D.; Brennan, Paul E. (June 2021). "The structural basis of fatty acid elongation by the ELOVL elongases". Nature Structural & Molecular Biology. 28 (6): 512–520. doi:10.1038/s41594-021-00605-6. ISSN   1545-9993. PMC   7611377 .
  13. ↑ Jump, Donald B. (2009). "Mammalian fatty acid elongases". Methods in Molecular Biology (Clifton, N.J.). 579: 375–389. doi:10.1007/978-1-60761-322-0_19. ISSN   1940-6029. PMC   2764369 . PMID   19763486.
  14. ↑ Jakobsson, A; Westerberg, R; Jacobsson, A (May 2006). "Fatty acid elongases in mammals: Their regulation and roles in metabolism" . Progress in Lipid Research. 45 (3): 237–249. doi:10.1016/j.plipres.2006.01.004. PMID   16564093.
  15. ↑ Kihara, A. (2012-11-01). "Very long-chain fatty acids: elongation, physiology and related disorders" . Journal of Biochemistry. 152 (5): 387–395. doi:10.1093/jb/mvs105. ISSN   0021-924X. PMID   22984005.
  16. 1 2 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". European Journal of Medical Research. 28 (1). doi: 10.1186/s40001-023-01523-7 . ISSN   2047-783X. PMC   10659008 . 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". Cell Metabolism. 36 (1): 36–47. doi: 10.1016/j.cmet.2023.11.017 . PMC   10843818 . PMID   38128528.
  19. 1 2 3 Nowinski, Sara M; Solmonson, Ashley; Rusin, Scott F; Maschek, J Alan; Bensard, Claire L; Fogarty, Sarah; Jeong, Mi-Young; Lettlova, Sandra; Berg, Jordan A; Morgan, Jeffrey T; Ouyang, Yeyun; Naylor, Bradley C; Paulo, Joao A; Funai, Katsuhiko; Cox, James E (2020-08-17). "Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria". eLife. 9. doi: 10.7554/eLife.58041 . ISSN   2050-084X. PMC   7470841 . PMID   32804083.
  20. ↑ Nair, Remya R.; Koivisto, Henna; Jokivarsi, Kimmo; Miinalainen, Ilkka J.; Autio, Kaija J.; Manninen, Aki; Poutiainen, Pekka; Tanila, Heikki; Hiltunen, J. Kalervo; Kastaniotis, Alexander J. (2018-11-07). "Impaired Mitochondrial Fatty Acid Synthesis Leads to Neurodegeneration in Mice". The Journal of Neuroscience. 38 (45): 9781–9800. doi: 10.1523/JNEUROSCI.3514-17.2018 . ISSN   0270-6474. PMC   6595986 . 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". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1866 (12) 118540. doi: 10.1016/j.bbamcr.2019.118540 . PMID   31473256.
  22. 1 2 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". Cancer Letters. 435: 92–100. doi:10.1016/j.canlet.2018.08.006. PMC   6240910 . PMID   30102953.
  23. 1 2 3 Nicastro, Raffaele; Brohée, Laura; Alba, Josephine; Nüchel, Julian; Figlia, Gianluca; Kipschull, Stefanie; Gollwitzer, Peter; Romero-Pozuelo, Jesus; Fernandes, Stephanie A.; Lamprakis, Andreas; Vanni, Stefano; Teleman, Aurelio A.; De Virgilio, Claudio; Demetriades, Constantinos (September 2023). "Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor". Nature Cell Biology. 25 (9): 1303–1318. doi: 10.1038/s41556-023-01198-6 . ISSN   1465-7392. PMC   10495264 . PMID   37563253.
  24. ↑ Talley, Jacob T.; Mohiuddin, Shamim S. (2025), "Biochemistry, Fatty Acid Oxidation", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   32310462 , retrieved 2025-11-12
  25. 1 2 van Weeghel, Michel; Abdurrachim, Desiree; Nederlof, Rianne; Argmann, Carmen A; Houtkooper, Riekelt H; Hagen, Jacob; Nabben, Miranda; Denis, Simone; Ciapaite, Jolita; Kolwicz, Stephen C; Lopaschuk, Gary D; Auwerx, Johan; Nicolay, Klaas; Des Rosiers, Christine; Wanders, Ronald J (2018-08-01). "Increased cardiac fatty acid oxidation in a mouse model with decreased malonyl-CoA sensitivity of CPT1B" . Cardiovascular Research. 114 (10): 1324–1334. doi:10.1093/cvr/cvy089. ISSN   0008-6363. PMID   29635338.
  26. ↑ Colak, Gozde; Pougovkina, Olga; Dai, Lunzhi; Tan, Minjia; te Brinke, Heleen; Huang, He; Cheng, Zhongyi; Park, Jeongsoon; Wan, Xuelian; Liu, Xiaojing; Yue, Wyatt W.; Wanders, Ronald J.A.; Locasale, Jason W.; Lombard, David B.; de Boer, Vincent C.J. (November 2015). "Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation". Molecular & Cellular Proteomics. 14 (11): 3056–3071. doi: 10.1074/mcp.M115.048850 . PMC   4638046 . PMID   26320211.
  27. ↑ Peng, Chao; Lu, Zhike; Xie, Zhongyu; Cheng, Zhongyi; Chen, Yue; Tan, Minjia; Luo, Hao; Zhang, Yi; He, Wendy; Yang, Ke; Zwaans, Bernadette M.M.; Tishkoff, Daniel; Ho, Linh; Lombard, David; He, Tong-Chuan (December 2011). "The First Identification of Lysine Malonylation Substrates and Its Regulatory Enzyme". Molecular & Cellular Proteomics. 10 (12) M111.012658. doi: 10.1074/mcp.M111.012658 . PMC   3237090 . PMID   21908771.
  28. ↑ Hirschey, Matthew D.; Zhao, Yingming (September 2015). "Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation". Molecular & Cellular Proteomics. 14 (9): 2308–2315. doi: 10.1074/mcp.R114.046664 . PMC   4563717 . 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 38318. doi: 10.1038/srep38318 . ISSN   2045-2322. PMC   5133563 . PMID   27910954.
  30. ↑ Du, Yipeng; Cai, Tanxi; Li, Tingting; Xue, Peng; Zhou, Bo; He, Xiaolong; Wei, Peng; Liu, Pingsheng; Yang, Fuquan; Wei, Taotao (January 2015). "Lysine malonylation is elevated in type 2 diabetic mouse models and enriched in metabolic associated proteins". Molecular & cellular proteomics: MCP. 14 (1): 227–236. doi: 10.1074/mcp.M114.041947 . ISSN   1535-9484. PMC   4288257 . PMID   25418362.
  31. ↑ Zou, Lu; Yang, Yanyan; Wang, Zhibin; Fu, Xiuxiu; He, Xiangqin; Song, Jiayi; Li, Tianxiang; Ma, Huibo; Yu, Tao (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. PMC   9937698 . PMID   36818560.
  32. 1 2 NIH Intramural Sequencing Center Group; Sloan, Jennifer L; Johnston, Jennifer J; Manoli, Irini; Chandler, Randy J; Krause, Caitlin; Carrillo-Carrasco, Nuria; Chandrasekaran, Suma D; Sysol, Justin R; O'Brien, Kevin; Hauser, Natalie S; Sapp, Julie C; Dorward, Heidi M; Huizing, Marjan; Barshop, Bruce A (September 2011). "Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria". Nature Genetics. 43 (9): 883–886. doi:10.1038/ng.908. ISSN   1061-4036. PMC   3163731 . PMID   21841779.
  33. ↑ "Orphanet: Malonic aciduria". www.orpha.net. Retrieved 2025-11-12.
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