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
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDBPDBePDBsum
Gene Ontology	AmiGO /QuickGO
Search PMC articles PubMed articles NCBI proteins

Acetyl-CoA carboxylase (ACC) is abiotin-dependentenzyme (EC6.4.1.2) that catalyzes the irreversiblecarboxylation ofacetyl-CoA to producemalonyl-CoA through its two catalytic activities,biotin carboxylase (BC) andcarboxyltransferase (CT). ACC is a multi-subunit enzyme in mostprokaryotes and in thechloroplasts of most plants and algae, whereas it is a large, multi-domain enzyme in thecytoplasm of mosteukaryotes. The most important function of ACC is to provide the malonyl-CoA substrate for thebiosynthesis of fatty acids.^[1] The activity of ACC can be controlled at the transcriptional level as well as by small molecule modulators andcovalent modification. The human genome contains the genes for two different ACCs^[2]—ACACA^[3] andACACB.^[4]

Prokaryotes andplants 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 ACCholoenzyme differs amongst organisms.^[1] Humans and mosteukaryotes 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 theN-terminus toC-terminus are the biotin carboxylase (BC), biotin binding (BB), carboxyl transferase (CT), andATP-binding (AB). AB lies within BC.Biotin is covalently attached through an amide bond to the longside 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 amitochondrial targeting sequence.^[1]

The polypeptides composing the multi-subunit ACCs ofprokaryotes andplants are encoded by distinct genes. InEscherichia coli,accA encodes the alpha subunit of the acetyl-CoA carboxylase,^[6] andaccD encodes its beta subunit.^[7]

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 ofbiotin withbicarbonate serving as the source of CO₂. The carboxyl group is transferred frombiotin toacetyl-CoA to formmalonyl-CoA in the second reaction, which is catalyzed by CT.

In theactive 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 theATP, and are required for ATP binding to the enzyme. Bicarbonate isdeprotonated by Glu296, although in solution, this proton transfer is unlikely as thepKa 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 anucleophile 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 resultingenolate 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 tocarnitine withcarnitine acyltransferase, which inhibits thebeta-oxidation of fatty acids in themitochondria.

Inmammals, two mainisoforms of ACC are expressed, ACC1 and ACC2, which differ in both tissue distribution and function. ACC1 is found in thecytoplasm of all cells but is enriched in lipogenic tissue, such asadipose tissue and lactatingmammary glands, where fatty acid synthesis is important.^[10] In oxidative tissues, such as theskeletal muscle and theheart, the ratio of ACC2 expressed is higher. ACC1 and ACC2 are both highly expressed in theliver where both fatty acid oxidation and synthesis are important.^[11] The differences in tissue distribution indicate that ACC1 maintains regulation offatty acid synthesis whereas ACC2 mainly regulates fatty acid oxidation (beta oxidation).

A mitochondrial isoform of ACC1 (mtACC1) plays a partially redundant role inlipoic acid synthesis and thus in protein lipoylation by providing malonyl-CoA formitochondrial fatty acid synthesis (mtFAS) in tandem withACSF3.^[12][13]

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 multiplepromoters which mediate ACC abundance in response to the cells nutritional status. Activation of gene expression through different promoters results inalternative splicing; however, the physiological significance of specific ACCisozymes remains unclear.^[11] The sensitivity to nutritional status results from the control of these promoters bytranscription factors such assterol regulatory element-binding protein 1, controlled by insulin at the transcriptional level, andChREBP, which increases in expression with highcarbohydrates diets.^[15][16]

Through a feed-forward loop,citrate allosterically activates ACC.^[17] Citrate may increase ACCpolymerization 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 includeglutamate and otherdicarboxylic acids.^[18] Long and short chain fatty acyl-CoAs arenegative feedback inhibitors of ACC.^[19] One such negative allosteric modulator ispalmitoyl-CoA.^[20]

Phosphorylation can result when the hormonesglucagon^[21] orepinephrine^[22] bind to cell surfacereceptors, 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 theAMP-activated protein kinase (AMPK). AMPK is the mainkinase 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]

Wheninsulin binds to its receptors on thecellular membrane, it activates a phosphatase enzyme calledprotein 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 themorpheein model ofallosteric regulation.^[26]

At the juncture of lipid synthesis and oxidation pathways, ACC presents many clinical possibilities for the production of novelantibiotics and the development of new therapies fordiabetes,obesity, and other manifestations ofmetabolic 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 companyGilead as part of a combination treatment fornon-alcoholic steatohepatitis (NASH), believed to be an increasing cause of liver failure.^[31]

In addition, plant-selective ACC inhibitors are in widespread use asherbicides,^[32] which suggests clinical application againstApicomplexa parasites that rely on a plant-derived ACC isoform,^[33] includingmalaria.

ACC inhibitors inIRAC group 23 are used asinsecticides /acaricides.^[34]

The heterogeneous clinical phenotypes of the metabolic diseasecombined malonic and methylmalonic aciduria (CMAMMA) due toACSF3 deficiency are thought to result from partial compensation of a mitochondrial isoform of ACC1 (mtACC1) for deficient ACSF3 inmitochondrial fatty acid synthesis (mtFAS).^[35]

• ACCase inhibitor herbicides
• Malonyl-CoA decarboxylase

• Genes on human chromosome 17
• Genes on human chromosome 12
• EC 6.4.1

• Articles with short description
• Short description is different from Wikidata
• Protein pages needing a picture
• All articles with unsourced statements
• Articles with unsourced statements from October 2018