Acetyl-CoA carboxylase

Acetyl-CoA carboxylase
EC number
CAS number 9023-93-2
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Acetyl-CoA carboxylase alpha
Symbol ACACA
Alt. symbols ACAC, ACC1, ACCA
Entrez 31
OMIM 601557
RefSeq NM_198839
UniProt Q13085
Other data
EC number
Locus Chr. 17 q21
Acetyl-CoA carboxylase beta
Symbol ACACB
Alt. symbols ACC2, ACCB
Entrez 32
OMIM 200350
RefSeq NM_001093
UniProt O00763
Other data
EC number
Locus Chr. 12 q24.1

Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes and in the chloroplasts of most plants and algae, whereas it is a large, multi-domain enzyme in the endoplasmic reticulum of most eukaryotes. The most important function of ACC is to provide the malonyl-CoA substrate for the biosynthesis of fatty acids.[1] The activity of ACC can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. The human genome contains the genes for two different ACCs[2]ACACA[3] and ACACB.[4]


Prokaryotes and plants have multi-subunit ACCs composed of several polypeptides encoded by distinct genes. Biotin carboxylase (BC) activity, biotin carboxyl carrier protein (BCCP), and carboxyl transferase (CT) activity are each contained on a different subunit. The stoichiometry of these subunits in the ACC holoenzyme differs amongst organisms.[1] Humans and most eukaryotes have evolved an ACC with CT and BC catalytic domains and biotin carboxyl carrier domains on a single polypeptide. ACC functional regions, starting from the N-terminus to C-terminus are the biotin carboxylase (BC), biotin binding (BB), carboxyltransferase (CT), and ATP-binding (AB). AB lies within BC. Biotin is covalently attached through an amide bond to the long side chain of a lysine reside in BB. As BB is between BC and CT regions, biotin can easily translocate to both of the active sites where it is required.

In mammals where two isoforms of ACC are expressed, the main structural difference between these isoforms is the extended ACC2 N-terminus containing a mitochondria targeting sequence.[1]

Crystallographic structures of E. coli acetyl-CoA carboxylase
Biotin carboxylase subunit of E. coli acetyl-CoA carboxylase 
Biotin carboxyl carrier protein subunit of E. coli acetyl-CoA carboxylase 
Carboxyl transferase subunit of E. coli acetyl-CoA carboxylase 


The overall reaction of ACAC(A,B) proceeds by a two-step mechanism.[5] The first reaction is carried out by BC and involves the ATP-dependent carboxylation of biotin with bicarbonate serving as the source of CO2. The carboxyl group is transferred from biotin to acetyl CoA to form malonyl CoA in the second reaction, which is catalyzed by CT.

In the active site, the reaction proceeds with extensive interaction of the residues Glu296 and positively charged Arg338 and Arg292 with the substrates.[6] Two Mg2+ are coordinated by the phosphate groups on the ATP, and are required for ATP binding to the enzyme. Bicarbonate is deprotonated by Glu296, although in solution, this proton transfer is unlikely as the pKa of bicarbonate is 10.3. The enzyme apparently manipulates pKas to facilitate the deprotonation of bicarbonate. The pKa of bicarbonate is decreased by its interaction with positively charged side chains of Arg338 and Arg292. Furthermore, Glu296 interacts with the side chain of Glu211, an interaction that has been shown to cause an increase in the apparent pKa. Following deprotonation of bicarbonate, the oxygen of the bicarbonate acts as a nucleophile and attacks the gamma phosphate on ATP. The carboxyphosphate intermediate quickly decomposes to CO2 and PO43−. The PO43− deprotonates biotin, creating an enolate, stabilized by Arg338, that subsequently attacks [[CO<sub>2</sub>]] resulting in the production of carboxybiotin.[6] The carboxybiotin translocates to the carboxytransferase (CT) active site, where the carboxyl group is transferred to acetyl-CoA. In contrast to the BC domain, little is known about the reaction mechanism of CT. A proposed mechanism is the release of carbon dioxide from biotin, which subsequently abstracts a proton from the methyl group from acetyl CoA carboxylase. The resulting enolate attacks CO2 to form malonyl CoA. In a competing mechanism, proton abstraction is concerted with the attack of acetyl CoA.


The function of ACC is to regulate the metabolism of fatty acids. When the enzyme is active, the product, malonyl-CoA, is produced which is a building block for new fatty acids and can inhibit the transfer of the fatty acyl group from acyl CoA to carnitine with carnitine acyltransferase, which inhibits the beta-oxidation of fatty acids in the mitochondria.

In mammals, two main isoforms of ACC are expressed, ACC1 and ACC2, which differ in both tissue distribution and function. ACC1 is found in the cytoplasm of all cells but is enriched in lipogenic tissue, such as adipose tissue and lactating mammary glands, where fatty acid synthesis is important.[7] In oxidative tissues, such as the skeletal muscle and the heart, the ratio of ACC2 expressed is higher. ACC1 and ACC2 are both highly expressed in the liver where both fatty acid oxidation and synthesis are important.[8] The differences in tissue distribution indicate that ACC1 maintains regulation of fatty acid synthesis whereas ACC2 mainly regulates fatty acid oxidation.


Control of Acetyl CoA Carboxylase. The AMP regulated kinase triggers the phosphorylation of the enzyme (thus inactivating it) and the phosphatase enzyme removes the phosphate group.

The regulation of mammalian ACC is complex, in order to control two distinct pools of malonyl CoA that direct either the inhibition of beta oxidation or the activation of lipid biosynthesis.[9]

Mammalian ACC1 and ACC2 are regulated transcriptionally by multiple promoters which mediate ACC abundance in response to the cells nutritional status. Activation of gene expression through different promoters results in alternative splicing; however, the physiological significance of specific ACC isozymes remains unclear.[8] The sensitivity to nutritional status results from the control of these promoters by transcription factors such as SREBP1c, controlled by insulin at the transcriptional level, and ChREBP, which increases in expression with high carbohydrates diets.[10][11]

Through a feedforward loop, citrate allosterically activates ACC.[12] Citrate may increase ACC polymerization to increases enzymatic activity; however, it is unclear if polymerization is citrate's main mechanism of increasing ACC activity or if polymerization is an artifact of in vitro experiments. Other allosteric activators include glutamate and other dicarboxylic acids.[13] Long and short chain fatty acyl CoAs are negative feedback inhibitors of ACC.[14]

Phosphorylation can result when the hormones glucagon or epinephrine bind to cell surface receptors, but the main cause of phosphorylation is due to a rise in AMP levels when the energy status of the cell is low, leading to the activation of the AMP-activated protein kinase (AMPK). AMPK is the main kinase regulator of ACC, able to phosphorylate a number of serine residues on both isoforms of ACC.[15] On ACC1, AMPK phosphorylates Ser79, Ser1200, and Ser1215. Protein kinase A also has the ability to phosphorylate ACC, with a much greater ability to phosphorylate ACC2 than ACC1. However, the physiological significance of protein kinase A in the regulation of ACC is currently unknown. Researchers hypothesize there are other ACC kinases important to its regulation as there are many other possible phosphorylation sites on ACC.[16]

When insulin binds to its receptors on the cellular membrane, it activates a phosphatase enzyme called protein phosphatase 2A (PP2A) to dephosphorylate the enzyme; thereby removing the inhibitory effect. Furthermore, insulin induces a phosphodiesterase that lowers the level of cAMP in the cell, thus inhibiting PKA, and also inhibits AMPK directly.

This protein may use the morpheein model of allosteric regulation.[17]

Clinical implications

At the juncture of lipid synthesis and oxidation pathways, ACC presents many clinical possibilities for the production of novel antibiotics and the development of new therapies for diabetes, obesity, and other manifestations of metabolic syndrome.[18] Researchers aim to take advantage of structural differences between bacterial and human ACCs to create antibiotics specific to the bacterial ACC, in efforts to minimize side effects to patients. Promising results for the usefulness of an ACC inhibitor include the finding that ACC2 -/- mice (mice with no expression of ACC2) have continuous fatty acid oxidation, reduced body fat mass, and reduced body weight despite an increase in food consumption. ACC2 -/- mice are also protected from diabetes.[9] It should be noted that a lack of ACC1 in mutant mice is lethal already at the embryonic stage. However, it is unknown whether drugs targeting ACCs in humans must be specific for ACC2.[19] An allosteric inhibitor of ACC has been granted fast-track status for the treatment of NASH (non-alcoholic steatohepatitis).[20]

See also


  1. 1 2 3 Tong L (August 2005). "Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery". Cell. Mol. Life Sci. 62 (16): 1784–803. doi:10.1007/s00018-005-5121-4. PMID 15968460.
  2. Brownsey RW, Zhande R, Boone AN (November 1997). "Isoforms of acetyl-CoA carboxylase: structures, regulatory properties and metabolic functions". Biochem. Soc. Trans. 25 (4): 1232–8. PMID 9449982.
  3. Abu-Elheiga L, Jayakumar A, Baldini A, Chirala SS, Wakil SJ (April 1995). "Human acetyl-CoA carboxylase: characterization, molecular cloning, and evidence for two isoforms". Proc. Natl. Acad. Sci. U.S.A. 92 (9): 4011–5. doi:10.1073/pnas.92.9.4011. PMC 42092Freely accessible. PMID 7732023.
  4. Widmer J, Fassihi KS, Schlichter SC, Wheeler KS, Crute BE, King N, Nutile-McMenemy N, Noll WW, Daniel S, Ha J, Kim KH, Witters LA (June 1996). "Identification of a second human acetyl-CoA carboxylase gene". Biochem. J. 316. ( Pt 3): 915–22. PMC 1217437Freely accessible. PMID 8670171.
  5. Lee CK, Cheong HK, Ryu KS, Lee JI, Lee W, Jeon YH, Cheong C (August 2008). "Biotinoyl domain of human acetyl-CoA carboxylase: Structural insights into the carboxyl transfer mechanism". Proteins. 72 (2): 613–24. doi:10.1002/prot.21952. PMID 18247344.
  6. 1 2 Chou CY, Yu LP, Tong L (April 2009). "Crystal structure of biotin carboxylase in complex with substrates and implications for its catalytic mechanism". J. Biol. Chem. 284 (17): 11690–7. doi:10.1074/jbc.M805783200. PMC 2670172Freely accessible. PMID 19213731.
  7. Kim TS, Leahy P, Freake HC (August 1996). "Promoter usage determines tissue specific responsiveness of the rat acetyl-CoA carboxylase gene". Biochem. Biophys. Res. Commun. 225 (2): 647–53. doi:10.1006/bbrc.1996.1224. PMID 8753813.
  8. 1 2 Barber MC, Price NT, Travers MT (March 2005). "Structure and regulation of acetyl-CoA carboxylase genes of metazoa". Biochim. Biophys. Acta. 1733 (1): 1–28. doi:10.1016/j.bbalip.2004.12.001. PMID 15749055.
  9. 1 2 L Abu-Elheiga; M M Matzuk; K A Abo-Hashema; S J Wakil (March 2001). "Continuous Fatty Acid Oxidation and Reduced Fat Storage in Mice Lacking Acetyl-CoA Carboxylase 2". Science. 291 (5513): 2613–6. doi:10.1126/science.1056843. PMID 11283375.
  10. Field F. J.; Born E.; Murthy S.; Mathur S. N. (December 2002). "Polyunsaturated fatty acids decrease the expression of sterol regulatory element binding protein-1 in CaCo-2 cells: effect on fatty acid synthesis and triacylglycerol transport.". Biochem. J. 368 (Pt 3): 855–64. doi:10.1042/BJ20020731. PMC 1223029Freely accessible. PMID 12213084.
  11. Ishii S, Iizuka K, Miller BC, Uyeda K (October 2004). "Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription". Proc Natl Acad Sci USA. 101 (44): 15597–602. doi:10.1073/pnas.0405238101. PMC 524841Freely accessible. PMID 15496471.
  12. Martin DB, Vagelos PR (June 1962). "The Mechanism of Tricarboxylic Acid Cycle Regulation of Fatty Acid Synthesis". J Biol Chem. 237: 1787–92. PMID 14470343.
  13. Boone AN, Chan A, Kulpa JE, Brownsey RW (April 2000). "Bimodal Activation of Acetyl-CoA Carboxylase by Glutamate". J Biol Chem. 275 (15): 10819–25. doi:10.1074/jbc.275.15.10819. PMID 10753875.
  14. Faergeman NJ, Knudsen J (April 1997). "Role of long chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling". Biochem J. 323 (Pt 1): 1–12. PMC 1218279Freely accessible. PMID 9173866.
  15. Park SH, Gammon SR, Knippers JD, Paulsen SR, Rubink DS, Winder WW (June 2002). "Phosphorylation-activity relationships of AMPK and acetyl-CoA carboxylase in muscle". J. Appl. Physiol. 92 (6): 2475–82. doi:10.1152/japplphysiol.00071.2002. PMID 12015362.
  16. Brownsey RW, Boone AN, Elliott JE, Kulpa JE, Lee WM (April 2006). "Regulation of acetyl-CoA carboxylase". Biochem. Soc. Trans. 34 (Pt 2): 223–7. doi:10.1042/BST20060223. PMID 16545081.
  17. T. Selwood; E. K. Jaffe. (2011). "Dynamic dissociating homo-oligomers and the control of protein function.". Arch. Biochem. Biophys. 519 (2): 131–43. doi:10.1016/ PMC 3298769Freely accessible. PMID 22182754.
  18. Corbett JW, Harwood JH (November 2007). "Inhibitors of mammalian acetyl-CoA carboxylase". Recent Patents Cardiovasc Drug Discov. 2 (3): 162–80. doi:10.2174/157489007782418928. PMID 18221116.
  19. Lutfi Abu-Elheiga; Martin M Matzuk; Parichher Kordari; WonKeun Oh; Tattym Shaikenov; Ziwei Gu; Salih J Wakil (August 2005). "Mutant Mice Lacking Acetyl CoA Carboxylase are Embryonically Lethal". Proc. Natl. Acad. Sci. USA. 102 (34): 1211–6. doi:10.1073/pnas.0505714102. PMC 1189351Freely accessible. PMID 16103361.

Further reading

  • Voet, Donald; Voet, Judith G. (2004). Biochemistry (3rd ed.). Wiley. ISBN 0-471-19350-X. 
  • edited by (2000). Buchanan, Bob B.; Gruissem, Wilhelm; Jones, Russell L., eds. Biochemistry and molecular biology of plants. American Society of Plant Physiologists. ISBN 0-943088-37-2. 
  • Levert K, Waldrop G, Stephens J (2002). "A biotin analog inhibits acetyl-CoA carboxylase activity and adipogenesis". J. Biol. Chem. 277 (19): 16347–50. doi:10.1074/jbc.C200113200. PMID 11907024. 
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