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acetyl-CoA carboxylase
Human ACC1 homodimer with catalytic domains highlighted; biotin carboxylase (red), biotinyl-binding (blue) and carboxyltransferase (green). PDB: 6G2D​
Identifiers
EC no.6.4.1.2
CAS no.9023-93-2
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
Acetyl-CoA carboxylase alpha
Identifiers
SymbolACACA
Alt. symbolsACAC, ACC1, ACCA
NCBI gene31
HGNC84
OMIM601557
RefSeqNM_198839
UniProtQ13085
Other data
EC number6.4.1.2
LocusChr. 17 q21
Search for
StructuresSwiss-model
DomainsInterPro
Acetyl-CoA carboxylase beta
Identifiers
SymbolACACB
Alt. symbolsACC2, ACCB
NCBI gene32
HGNC85
OMIM200350
RefSeqNM_001093
UniProtO00763
Other data
EC number6.4.1.2
LocusChr. 12 q24.1
Search for
StructuresSwiss-model
DomainsInterPro

Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme (EC 6.4.1.2) 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 cytoplasm 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]

Structure

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Prokaryotes and plants have multi-subunit ACCs composed of several polypeptides. 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 BCCP domains on a single polypeptide. Most plants also have this homomeric form in cytosol.[5] ACC functional regions, starting from the N-terminus to C-terminus are the biotin carboxylase (BC), biotin binding (BB), carboxyl transferase (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 mitochondrial targeting sequence.[1]

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

Genes

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The polypeptides composing the multi-subunit ACCs of prokaryotes and plants are encoded by distinct genes. In Escherichia coli, accA encodes the alpha subunit of the acetyl-CoA carboxylase,[6] and accD encodes its beta subunit.[7]

Mechanism

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The overall reaction of ACAC(A,B) proceeds by a two-step mechanism.[8] 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.

The reaction mechanism of ACAC(A,B).
  enzyme
  coenzymes
  substrate names
  metal ions
  phosphate
  carbonate

In the active site, the reaction proceeds with extensive interaction of the residues Glu296 and positively charged Arg338 and Arg292 with the substrates.[9] 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 the pKa 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 CO2 resulting in the production of carboxybiotin.[9] The carboxybiotin translocates to the carboxyl transferase (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 CO2 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.

Function

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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.[10] 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.[11] The differences in tissue distribution indicate that ACC1 maintains regulation of fatty acid synthesis whereas ACC2 mainly regulates fatty acid oxidation (beta oxidation).

A mitochondrial isoform of ACC1 (mtACC1) plays a partially redundant role in lipoic acid synthesis and thus in protein lipoylation by providing malonyl-CoA for mitochondrial fatty acid synthesis (mtFAS) in tandem with ACSF3.[12][13]

Regulation

[edit]
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.[14]

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.[11] The sensitivity to nutritional status results from the control of these promoters by transcription factors such as sterol regulatory element-binding protein 1, controlled by insulin at the transcriptional level, and ChREBP, which increases in expression with high carbohydrates diets.[15][16]

Through a feed-forward loop, citrate allosterically activates ACC.[17] Citrate may increase ACC polymerization to increase 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.[18] Long and short chain fatty acyl-CoAs are negative feedback inhibitors of ACC.[19] One such negative allosteric modulator is palmitoyl-CoA.[20]

Phosphorylation can result when the hormones glucagon[21] or epinephrine[22] 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.[23] 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. Ser80 and Ser1263 on ACC1 may also serve as a site of phosphorylation as a regulatory mechanism.[24] 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.[25]

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.[citation needed]

This protein may use the morpheein model of allosteric regulation.[26]

Clinical implications

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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.[27] 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 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. These mice are also protected from diabetes.[14] 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.[28]

Firsocostat (formerly GS-976, ND-630, NDI-010976) is a potent allosteric ACC inhibitor, acting at the BC domain of ACC.[29] Firsocostat is under development in 2019 (Phase II)[30] by the pharmaceutical company Gilead as part of a combination treatment for non-alcoholic steatohepatitis (NASH), believed to be an increasing cause of liver failure.[31]

In addition, plant-selective ACC inhibitors are in widespread use as herbicides,[32] which suggests clinical application against Apicomplexa parasites that rely on a plant-derived ACC isoform,[33] including malaria.

ACC inhibitors in IRAC group 23 are used as insecticides / acaricides.[34]

The heterogeneous clinical phenotypes of the metabolic disease combined malonic and methylmalonic aciduria (CMAMMA) due to ACSF3 deficiency are thought to result from partial compensation of a mitochondrial isoform of ACC1 (mtACC1) for deficient ACSF3 in mitochondrial fatty acid synthesis (mtFAS).[35]

See also

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Acetyl-CoA carboxylase

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from Grokipedia
Acetyl-CoA carboxylase (ACC) is a biotin-dependent that catalyzes the ATP-driven of to form , representing the first committed and rate-limiting step in de novo fatty acid . This reaction is essential for , as serves as a building block for fatty acid elongation and inhibits carnitine palmitoyltransferase 1 (CPT1), thereby regulating the balance between fatty acid synthesis and β-oxidation. In mammals, ACC exists as two distinct isoforms encoded by separate genes: ACC1 (encoded by ACACA on 17q12), a 265 cytosolic protein primarily responsible for in tissues such as liver and adipose, and ACC2 (encoded by ACACB on 12q23), a 275 protein anchored to the outer mitochondrial membrane that modulates fatty acid oxidation in oxidative tissues like heart and skeletal muscle. The two isoforms share approximately 75% amino acid sequence identity but differ in their N-terminal targeting sequences and subcellular localization. Structurally, ACC is a large multifunctional organized into three core domains: the biotin carboxylase (BC) domain, which uses ATP and to carboxylate the ; the biotin carboxyl carrier protein (BCCP) domain, which shuttles the activated carboxyl group; and the carboxyltransferase (CT) domain, which transfers the carboxyl moiety to . These domains enable a swinging arm mechanism for , and ACC functions as a homodimer that can polymerize into filaments, a critical for its activity. Cryo-electron microscopy studies have revealed that ACC1 forms dynamic filaments, where allosteric by citrate promotes an extended, catalytically active conformation, while inhibitory interactions—such as binding to the BRCA1 BRCT domain—induce a compact, inactive state. Regulation of ACC is multifaceted and tightly linked to cellular energy status, involving allosteric effectors, reversible phosphorylation, and protein-protein interactions. Citrate acts as a potent allosteric activator by promoting filament assembly and domain dimerization, whereas long-chain acyl-CoA esters like palmitoyl-CoA serve as feedback inhibitors. Phosphorylation by (AMPK) at specific serine residues (e.g., Ser-79 in ACC1) inactivates the enzyme during energy depletion, counteracting lipogenesis and favoring . Transcriptional control by factors such as SREBP-1c further modulates ACC expression in response to nutritional cues. Dysregulation of ACC activity contributes to metabolic diseases, including , , non-alcoholic fatty liver disease, and certain cancers, where ACC1 overexpression supports tumor growth and ACC2 inhibition enhances fatty acid utilization. As a result, ACC has emerged as a promising therapeutic target, with isoform-specific inhibitors under investigation for treating metabolic disorders. As of 2025, dual ACC1/2 inhibitors such as ervogastat are in Phase 2 and 3 clinical trials for metabolic dysfunction-associated steatotic liver disease (MASLD).

Molecular Structure and Genetics

Protein Architecture

Acetyl-CoA carboxylase (ACC) is a multifunctional complex that catalyzes the of to , featuring three core domains integrated into a single polypeptide chain in eukaryotic forms. The carboxylase (BC) domain, located at the , facilitates the ATP-dependent activation of to carboxyphosphate and subsequent of . The central carboxyl carrier protein (BCCP) domain serves as a flexible linker that covalently attaches , enabling its role as a mobile carboxyl carrier. The C-terminal carboxyltransferase (CT) domain transfers the carboxyl group from carboxy to , forming . ACC exhibits a hierarchical oligomeric organization critical for its catalytic activity, beginning with dimerization mediated by interactions between the BC domains of two monomers, which stabilizes the enzyme's core structure. These dimers further assemble into higher-order filamentous structures, often hundreds of nanometers in length, that are essential for full enzymatic function and are dynamically regulated. Cryo-electron microscopy (cryo-EM) studies of human ACC have revealed that these filaments adopt distinct conformations depending on the activation state; for instance, inactive filaments of ACC1 form compact, acetyl-CoA-bound assemblies, while citrate-induced active filaments extend into more elongated forms. Mammalian ACC exists in two isoforms with distinct subcellular localizations and structural features: ACC1, a 265 cytosolic enzyme primarily expressed in lipogenic tissues, and ACC2, at 280 , associated with the outer mitochondrial via an N-terminal extension containing a hydrophobic targeting . These isoform-specific extensions flank the conserved core domains but do not alter the fundamental BC-BCCP-CT architecture. The is covalently attached to a specific residue (Lys-2160 in ACC1) within the BCCP domain via an amide bond, a catalyzed by protein . This attachment positions on a flexible "swinging arm" extension of the BCCP, allowing it to shuttle between the distant BC and CT active sites—separated by up to 80 in the filament—facilitating the two-step reaction without requiring large-scale domain movements. Structural analyses of the BCCP domain highlight its compact β-sheet fold with a protruding thumb-like motif that interacts with partner domains during .

Encoding Genes and Isoforms

In humans, the ACACA , located on 17q12, encodes acetyl-CoA carboxylase 1 (ACC1), a cytosolic isoform primarily expressed in lipogenic tissues such as the liver and , where it supports de novo . The ACACB , mapped to 12q24.11, encodes acetyl-CoA carboxylase 2 (ACC2), a mitochondrial isoform predominantly expressed in oxidative tissues including the heart and . ACC1 functions to commit to by generating in the , serving as the committed step in . In contrast, ACC2 produces at the mitochondrial outer membrane, where it inhibits carnitine palmitoyltransferase-1 (CPT-1), thereby exerting control over beta-oxidation to prevent simultaneous synthesis and breakdown of lipids. The genetic organization of acetyl-CoA carboxylase (ACC) shows evolutionary conservation with structural diversity across kingdoms. In bacteria, such as , ACC exists as a multisubunit complex comprising separate polypeptides: AccA and AccD for the carboxyltransferase, AccB as the biotin carboxyl carrier protein, and AccC as the biotin carboxylase. Yeast employs a single encoding a large, multifunctional polypeptide similar to mammalian forms, while feature multisubunit ACC in plastids for and homodimeric cytosolic versions. In mammals, evolutionary fusion has resulted in two large, multifunctional polypeptides from distinct genes, reflecting adaptation for compartmentalized metabolic roles. Alternative splicing of ACACA and ACACB generates isoforms with variations, particularly in the N-terminal region, which may influence subcellular targeting or stability. Tissue-specific promoters drive their expression patterns, ensuring ACC1 predominance in anabolic tissues and ACC2 in catabolic ones. Rare biallelic mutations in ACACA disrupt lipid homeostasis and are linked to developmental disorders, while polymorphisms in ACACB associate with metabolic traits like and risk.

Catalytic Mechanism

Reaction Catalyzed

Acetyl-CoA carboxylase (ACC; EC 6.4.1.2) catalyzes the irreversible carboxylation of to form , a pivotal reaction in . The overall of the reaction is given by: [Acetyl-CoA](/page/Acetyl-CoA)+HCO3−+ATP→[Malonyl-CoA](/page/Malonyl-CoA)+ADP+Pi\text{[Acetyl-CoA](/page/Acetyl-CoA)} + \text{HCO}_3^- + \text{ATP} \rightarrow \text{[Malonyl-CoA](/page/Malonyl-CoA)} + \text{ADP} + \text{P}_\text{i} This transformation incorporates a carboxyl group from into , utilizing the energy released from to drive the process forward. The step itself is endergonic, but coupling to renders the overall reaction exergonic and essentially irreversible under physiological conditions, ensuring efficient production of despite an equilibrium that would otherwise favor the reactants. Cellular concentrations of substrates and rapid utilization of further shift the reaction toward product formation. In metabolic pathways, this reaction represents the first committed step in de novo fatty acid synthesis, supplying as the two-carbon donor for elongation by . Additionally, serves as a regulatory signal, allosterically inhibiting carnitine palmitoyltransferase 1 (CPT1) to prevent simultaneous fatty acid synthesis and mitochondrial β-oxidation. The reaction requires specific cofactors for catalysis: , which is covalently attached to the enzyme and acts as a mobile carboxyl carrier; Mg²⁺-complexed ATP as the phosphate donor; and CO₂ supplied as (HCO₃⁻). No additional enzymes are directly involved in this core , distinguishing it from downstream condensations in fatty acid assembly.

Enzymatic Steps

Acetyl-CoA carboxylase (ACC) catalyzes its reaction through two sequential partial reactions coordinated across its multi-domain architecture, with serving as a mobile carboxyl carrier. In the first step, the biotin carboxylase (BC) domain facilitates the carboxylation of , which is covalently attached to a residue on the biotin carboxyl carrier protein (BCCP) domain. This process utilizes ATP and (HCO₃⁻) as substrates, activating to carboxyphosphate and then carboxylating the N1' position of to form carboxybiotin, with the concomitant of ATP to ADP and inorganic (Pᵢ). The second step involves the carboxyltransferase (CT) domain, where the activated carboxybiotin swings to deliver the carboxyl group (as CO₂) to the α-carbon of , resulting in the formation of and the regeneration of free on BCCP. This transfer is precise, ensuring the form of is carboxylated without direct ATP involvement in this partial reaction. The translocation of between the distant BC and CT active sites relies on the swinging-arm model, in which the flexible linker of the BCCP domain (approximately 16 Å from the N1' to the Cα) enables movement, supplemented by translocation of the entire BCCP domain to bridge the ~55–85 Å separation observed in holoenzyme structures. This dynamic mechanism ensures efficient carboxyl group shuttling without dissociation of . Kinetic parameters for ACC reflect its regulatory context, with reported Kₘ values for ranging from ~5–40 μM in the activated state and ~100 μM for ATP, varying by species and activation conditions such as citrate or CoA presence. The Vₘₐₓ is modulated by the enzyme's oligomerization state, with filamentous assemblies enhancing catalytic efficiency through stabilized domain positioning that promotes BCCP translocation. Structural studies using inhibitors like haloxyfop, a targeting the CT domain, have illuminated key features, revealing that haloxyfop binds at the dimer interface and induces conformational changes in residues such as Tyr1738 and Phe1956, while highlighting the essential role of conserved Lys246 in stabilizing the intermediate during carboxyl transfer.

Physiological Roles

In Lipogenesis

Acetyl-CoA carboxylase 1 (ACC1) is primarily localized in the of lipogenic tissues, including the liver, , and lactating , particularly during the fed state when nutrient availability supports . In these organs, ACC1 utilizes derived from the of glucose and pyruvate; pyruvate generated from enters the mitochondria, where it is converted to , which then forms citrate and is exported to the via ATP-citrate lyase to provide the substrate for ACC1-mediated . This positioning enables ACC1 to channel carbon units from toward synthesis, serving as a key entry point for de novo (DNL). The produced by ACC1 acts as the essential two-carbon (C2) donor in the iterative cycles of (FAS), where it condenses with growing acyl chains to elongate them by two carbons per cycle, ultimately yielding palmitate and longer s for formation. Each FAS cycle involves of , ensuring efficient chain extension while preventing futile cycling. This process is fundamental to anabolic production, with levels directly influencing the rate and extent of fatty acid assembly. ACC1 catalyzes the rate-limiting step in DNL, committing acetyl-CoA to malonyl-CoA and thereby controlling the flux through the pathway; inhibition or knockdown of ACC1 substantially reduces fatty acid synthesis rates. In models of obesity, ACC1 expression and activity are upregulated, particularly in adipose and liver tissues, driving increased de novo fatty acid production that contributes to triglyceride storage and lipid accumulation. For instance, elevated ACC1 in subcutaneous adipose tissue of obese individuals correlates with enhanced DNL, promoting energy storage as lipids. In adipocytes, ACC1 supports the formation of lipid droplets by providing fatty acids for synthesis and esterification, facilitating the expansion of adipose mass during nutrient excess. In hepatocytes, ACC1-driven DNL contributes to the assembly of (VLDL) particles by supplying newly synthesized fatty acids for incorporation into B-containing lipoproteins for export. Quantitatively, in humans, hepatic ACC1 activity aligns with postprandial DNL rates, where DNL can account for up to 20-30% of VLDL- fatty acids in conditions of high intake or metabolic dysregulation, underscoring its role in partitioning.

In Fatty Acid Oxidation Control

Acetyl-CoA carboxylase 2 (ACC2) is primarily localized to the outer mitochondrial in oxidative tissues such as the heart, , and liver, where it generates in close proximity to its target enzyme. This positioning enables ACC2 to produce localized pools of that specifically regulate mitochondrial entry without broadly affecting cytosolic processes. In these tissues, ACC2's activity is crucial for controlling the balance between fat storage and utilization by modulating beta-oxidation. The produced by ACC2 acts as a potent allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT-1), the rate-limiting enzyme responsible for transporting long-chain into mitochondria for beta-oxidation. This inhibition occurs with high sensitivity, as binds CPT-1 with an IC50 in the range of 1-10 nM, effectively blocking shuttling and preventing futile cycling between and breakdown. By suppressing CPT-1, ACC2-derived ensures that fatty acids are directed toward storage rather than oxidation during nutrient-replete conditions. ACC2 plays a key role in metabolic switching between fed and fasting states, where its activity dictates the prioritization of energy pathways. In the fed state, elevated ACC2 activity increases levels, inhibiting CPT-1 and suppressing oxidation to favor storage from dietary carbohydrates. Conversely, during , ACC2 is inactivated—primarily through phosphorylation by (AMPK)—reducing and relieving CPT-1 inhibition to promote oxidation for energy production. This dynamic regulation prevents simultaneous and , optimizing . The compartmentalization of ACC2 on the mitochondrial outer membrane creates distinct microdomains where its product exerts targeted effects on nearby CPT-1 molecules, separate from the cytosolic pools generated by ACC1. This spatial organization enhances the efficiency of inhibition, as local concentrations near CPT-1 can reach inhibitory levels without significantly impacting distant cytosolic . Experimental evidence from ACC2 knockout mice underscores its role in controlling fatty acid oxidation. These mice exhibit chronically elevated CPT-1 activity and increased rates of beta-oxidation due to the absence of inhibitory , leading to higher energy expenditure and reduced fat accumulation. When challenged with a high-fat diet, ACC2-deficient mice demonstrate resistance to diet-induced , with lower body weight gain and improved metabolic profiles compared to wild-type controls. This highlights ACC2's essential function in preventing excessive fat oxidation under normal conditions while allowing adaptive increases during energy demand.

Regulation

Allosteric Mechanisms

Acetyl-CoA carboxylase (ACC) undergoes through non-covalent interactions with key metabolites that modulate its oligomeric state and enzymatic activity. Citrate serves as a primary activator, binding to the biotin carboxylase (BC) domain and inducing a conformational change that promotes the transition from inactive dimers to active filamentous polymers. This polymerization enhances ACC activity by more than 10-fold, reflecting the fed state where elevated citrate levels from mitochondrial export signal increased . The structural basis involves citrate stabilizing inter-domain contacts within the BC domain, locking the enzyme in a catalytically competent conformation as revealed by cryo-electron structures of the citrate-bound filament. In contrast, palmitoyl-CoA acts as an inhibitor by binding to the carboxyltransferase (CT) domain, disrupting filament assembly and causing to inactive protomers. This reduces the maximum (Vmax) of the , with an inhibitor constant (Ki) of approximately 1.7 μM for non-phosphorylated ACC, signaling excess lipid accumulation and feedback inhibition of . Structurally, palmitoyl-CoA binding to the CT domain alters inter-subunit interfaces, destabilizing the active filament and shifting ACC to an inactive state, as demonstrated in filament dissolution assays. Long-chain acyl-CoAs generally exhibit similar inhibitory effects, with potencies varying by length and saturation. In prokaryotes, acyl-acyl carrier proteins (acyl-ACPs), such as palmitoyl-ACP, provide analogous feedback inhibition, exhibiting pronounced in ACC and reducing activity to prevent overproduction of fatty acids. Both mammalian isoforms, ACC1 and ACC2, respond comparably to these effectors, with citrate promoting in each, though tissue-specific concentrations—higher citrate in lipogenic tissues for ACC1 and acyl-CoAs in oxidative tissues for ACC2—determine the net regulatory outcome.

Post-Translational Modifications

Acetyl-CoA carboxylase (ACC) undergoes several post-translational modifications that regulate its enzymatic activity, primarily through and events responsive to cellular energy status and hormonal signals. by () at Ser79 of ACC1 and Ser222 of ACC2 occurs during conditions of low energy, such as a decreased ATP:AMP ratio, leading to inhibition of ACC activity by 50-90% and suppression of . This modification disrupts the formation of active ACC filaments, preventing polymerization essential for catalytic efficiency. Additional phosphorylation by (PKA), triggered by or epinephrine, targets Ser1200 in ACC1, resulting in further inhibition that is additive to AMPK effects and reduces production. In contrast, () phosphorylation, associated with insulin signaling, may promote ACC activation by altering phosphorylation at distinct serine residues, though the net effect often contributes to the overall dephosphorylation-driven activation observed under fed conditions. Dephosphorylation of ACC is mediated by protein phosphatase 2A (PP2A), which removes inhibitory phosphates from sites like Ser79 in ACC1, restoring enzymatic activity and enabling filament reformation in response to insulin during nutrient abundance. Insulin stimulates this process by enhancing PP2A activity, thereby reactivating ACC and promoting . Ubiquitination targets ACC for proteasomal degradation, particularly ACC1, with factors like malonylation reducing ubiquitination to stabilize the enzyme and sustain in pathological states such as hepatic . These site-specific modifications link ACC regulation to broader metabolic control, with phosphorylated forms showing increased sensitivity to allosteric inhibitors.

Clinical Relevance

Involvement in Diseases

Dysregulation of acetyl-CoA carboxylase (ACC) isoforms contributes to various metabolic and proliferative disorders, with ACC1 primarily implicated in excessive lipogenesis and ACC2 in altered fatty acid oxidation. In metabolic syndrome, ACC1 overexpression in the liver of individuals with obesity and type 2 diabetes enhances de novo lipogenesis, leading to hepatic steatosis and insulin resistance. Conversely, ACC2 deficiency in mouse models protects against diet-induced obesity and insulin resistance by increasing fatty acid oxidation and reducing fat accumulation. In non-alcoholic fatty liver disease (NAFLD), also known as metabolic dysfunction-associated steatotic liver disease (MASLD), elevated ACC activity, particularly ACC1, drives de novo lipogenesis, which accounts for approximately 26% of hepatic triglycerides in affected patients. This upregulation contributes to progression, and while specific genetic variants in the ACACA gene (encoding ACC1) have been explored, broader lipogenic pathway polymorphisms influence disease severity. In cancer, ACC1 supports tumor by providing for synthesis and signaling pathways, as observed in and cancers where its inhibition reduces and . ACC2 loss, on the other hand, can promote a Warburg-like metabolic shift favoring and tumor survival under stress, as seen in models where its suppression enhances oxidation but alters overall metabolic flexibility. Cardiovascular diseases involve ACC2-mediated malonyl-CoA regulation of cardiac fuel switching between glucose and fatty acids; its dysregulation during ischemia-reperfusion impairs mitochondrial function and exacerbates myocardial damage, while ACC2 deletion in mice reduces levels and protects against ischemic outcomes. Rare monogenic disorders, such as acetyl-CoA carboxylase-alpha deficiency (ACACAD) caused by biallelic ACACA mutations, manifest as autosomal recessive conditions with , global developmental delay, and due to impaired de novo . Additionally, mitochondrial isoforms of ACC1 have been linked to neurodegeneration, with mutations in related pathways contributing to progressive neurological decline.

Therapeutic Strategies

Pharmacological modulation of (ACC) has emerged as a promising for treating metabolic disorders such as metabolic dysfunction-associated (MASLD) and nonalcoholic (NASH), as well as oncologic conditions driven by aberrant synthesis. Dual inhibitors targeting both ACC1 and ACC2 isoforms inhibit de novo while potentially enhancing oxidation, leading to reduced hepatic accumulation. For instance, ND-630 (also known as GS-0976 or firsocostat), a potent dual ACC inhibitor, demonstrated significant reductions in hepatic de novo (by approximately 22%) and in phase 2 trials for NASH patients after 12 weeks of treatment, with liver fat content decreasing by up to 30-50% in responders. Similarly, PF-05221304 (clesacostat), a liver-targeted dual inhibitor, reduced hepatic fat by 30-48% in phase 1/2 studies of NAFLD patients, alongside improvements in profiles and no major safety signals at therapeutic doses. These agents block production, thereby suppressing and alleviating in preclinical and early clinical models. Isoform-selective inhibitors address limitations of dual agents by minimizing off-target effects on ACC2, which can lead to . ACC1-specific inhibitors, such as ND-630 (with 3-fold selectivity for ACC1 over ACC2), have shown efficacy in cancer models by disrupting lipid-dependent tumor growth without broadly impairing mitochondrial oxidation; for example, selective ACC1 inhibition reduced levels and tumor proliferation in xenografts. In contrast, strategies to enhance oxidation via ACC2 modulation typically involve inhibition rather than agonism, as ACC2 knockout or pharmacological blockade in rodent models increases β-oxidation rates by 30% in and protects against diet-induced . Emerging ACC1-selective compounds, like those identified in high-throughput screens, are being developed for , targeting ACC1's role in providing for biogenesis in proliferating cancer cells. Clinical trials of ACC inhibitors for NASH have yielded mixed results, with monotherapy often limited by adverse effects but combinations showing promise. GSK-0976 monotherapy in phase 2 trials reduced liver injury markers but was associated with dose-dependent elevations in plasma triglycerides (median increases of 11-13%), including cases of grade 3-4 , attributed to ACC2 inhibition disrupting carnitine palmitoyltransferase-1 regulation. As of 2025, combination therapies involving GSK-0976 and GLP-1 receptor agonists or statins are under evaluation in phase 2b studies to mitigate while enhancing resolution; preliminary data indicate improvements in NASH histology without severe . Dual inhibition approaches in MASLD trials, including PF-05221304 combined with diacylglycerol acyltransferase 2 inhibitors, have achieved up to 50% reductions in phase 2 settings by 2023, supporting further evaluation in advanced cohorts. Key challenges in ACC inhibitor include and from ACC2 blockade, which elevates circulating triglycerides by inhibiting peripheral oxidation. Structural insights from cryo-electron (cryo-EM) studies, such as the 2024 resolution of human ACC1 filaments revealing dynamic dimerization interfaces, have informed rational to improve isoform selectivity and reduce off-target effects. These structures highlight allosteric sites for inhibitor binding, guiding the of molecules that spare ACC2 while potently inhibiting ACC1. Emerging therapeutic avenues include gene therapies targeting the ACACA gene (encoding ACC1) to suppress in models. Preclinical studies using AAV-mediated ACACA knockdown in obese mice reduced hepatic accumulation via AMPK-PPARα pathway activation, decreasing body weight by 15-20% without affecting food intake. Additionally, structural analogies from and ACC cryo-EM models have accelerated development, such as ACC-inhibiting aryloxyphenoxypropionates used in , providing templates for isoform-specific modulators.

References

  1. https://tonglab.biology.columbia.edu/Research/acc.shtml
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC8963101/
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