ACC

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Acetyl CoA carboxylase (Acetyl CoA carboxylase) catalyzes the biotinase reaction of acetyl-CoA+ATP+HCO₃-→malonyl-CoA+ADP+Pi. Exist widely in the biological world. This reaction restricts the speed of the first stage of fatty acid synthesis. This reaction consists of two steps, that is, the reaction of using ATP to fix CO₂ on the biotin bound to the enzyme and transferring CO₂ to acetyl-CoA. The enzymes in E. coli or plants can be divided into proteins that catalyze these two reactions and proteins that bind biotin, while the enzymes in animals or yeasts cannot be separated. Animal enzymes are allosteric enzymes. The body does not show activity, while the polymer that polymerizes into fibrous form shows activity. Animals change the rate of fatty acid synthesis due to different nutritional and hormone conditions, and this enzyme plays a major role in the regulation of this change.

Structures

The stoichiometry of these subunits in ACC holoenzyme varies from organism to organism. Humans and most eukaryotes have evolved ACC with CT and BC catalytic domains and BCCP domains on a single polypeptide. Most plants also have this isomeric form in the cytoplasm. The ACC functional area from N-terminal to C-terminal is biotin carboxylase (BC), biotin binding (BB), carboxyl transferase (CT) and ATP binding (AB). AB is located in BC. Biotin is covalently linked to the long side chain of lysine in BB through an amide bond. Since BB is located between the BC and CT regions, biotin can be easily transferred to the two active sites where it is needed. In mammals expressing the two ACC subtypes, the main structural difference between these subtypes is the extended ACC2 N-terminus containing the mitochondrial targeting sequence.

Functions

The function of ACC is to regulate fatty acid metabolism. When the enzyme is active, the produced product malonyl-CoA is a component of the new fatty acid, and can inhibit the transfer of fatty acyl groups from acyl-CoA to carnitine by carnitine acyltransferase, thereby inhibiting the oxidation of β-oxidase. Fatty acids in mitochondria. In mammals, two main subtypes of ACC are expressed, namely ACC1 and ACC2, which are different in tissue distribution and function. ACC1 is found in the cytoplasm of all cells, but fat-rich tissues (such as adipose tissue and lactating mammary glands) are important in fat synthesis. In oxidized tissues such as skeletal muscle and heart, the expression ratio of ACC2 is higher. Both ACC1 and ACC2 are highly expressed in the liver, and the oxidation and synthesis of fatty acids are both important. The difference in tissue distribution indicates that ACC1 maintains the regulation of fatty acid synthesis, while ACC2 mainly regulates fatty acid oxidation (β oxidation).

Regulations

Mammalian ACC1 and ACC2 are transcriptionally regulated by a variety of promoters, and these promoters mediate the abundance of ACC in response to the nutritional status of the cell. Activation of gene expression by different promoters can lead to alternative splicing; however, the physiological significance of specific ACC isoenzymes is unclear. Sensitivity to nutritional status comes from the control of these promoters by transcription factors, such as sterol regulatory element binding protein 1 (controlled by insulin at the transcription level) and ChREBP (increased expression in a high-carbohydrate diet). When insulin binds to receptors on its cell membrane, it activates a phosphatase called protein phosphatase 2A (PP2A) to dephosphorylate the enzyme. Thereby eliminating the inhibitory effect. In addition, insulin induces phosphodiesterase to reduce the level of cAMP in cells, thereby inhibiting PKA and directly inhibiting AMPK.

Clinical significance

At the juncture of lipid synthesis and oxidation pathways, ACC provides many clinical possibilities for the production of new antibiotics and the development of new treatments for diabetes, obesity and other manifestations of metabolic syndrome. Promising results useful for ACC inhibitors include the finding that despite increased food consumption, mice without ACC2 expression have continuous fatty acid oxidation, decreased body fat mass, and decreased body weight. These mice can also prevent diabetes.