Acetyl-CoA carboxylase

covalent modification. The human genome contains the genes for two different ACCs^[2]—ACACA^[3] and ACACB.^[4]

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

mitochondrial targeting sequence.^[1]

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]

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

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

carbohydrates diets.^[15][16]

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]

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]

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}

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]

non-alcoholic steatohepatitis (NASH), believed to be an increasing cause of liver failure.^[31]