Acetyl-CoA carboxylase

Acetyl-CoA Carboxylase (ACC) is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA, a critical step in fatty acid synthesis and fatty acid oxidation. This enzyme plays a pivotal role in lipid metabolism and is found in all eukaryotes, including humans, as well as in many prokaryotes.

Function

Acetyl-CoA Carboxylase is involved in the first step of fatty acid synthesis. It converts acetyl-CoA to malonyl-CoA, using ATP and carbon dioxide as substrates. Malonyl-CoA is then used as a carbon source for the elongation of fatty acid chains in the cytoplasm of cells. In fatty acid oxidation, malonyl-CoA inhibits carnitine palmitoyltransferase 1 (CPT1), a transporter that moves long-chain fatty acids into the mitochondria for oxidation, thus regulating fatty acid oxidation based on the cell's metabolic needs.

Structure

ACC exists in two isoforms, ACC1 and ACC2, encoded by two different genes. ACC1 is primarily found in lipogenic tissues such as the liver and adipose tissue, where it is involved in fatty acid synthesis. ACC2 is located on the outer mitochondrial membrane, where it regulates fatty acid oxidation by controlling the levels of malonyl-CoA.

The enzyme is composed of four domains: the biotin carboxylase (BC) domain, the biotin carboxyl carrier protein (BCCP) domain, the carboxyltransferase (CT) domain, and a regulatory domain that controls enzyme activity through phosphorylation.

Regulation

The activity of Acetyl-CoA Carboxylase is regulated by both allosteric controls and covalent modification (phosphorylation). Allosterically, it is activated by citrate, which signals the abundance of substrates for fatty acid synthesis, and inhibited by long-chain fatty acyl-CoAs, indicating sufficient fatty acid levels. Phosphorylation of ACC by AMP-activated protein kinase (AMPK) inactivates the enzyme, reducing fatty acid synthesis and promoting fatty acid oxidation, especially during times of low energy availability.

Clinical Significance

Due to its central role in lipid metabolism, ACC is a target for the development of drugs to treat metabolic disorders such as obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). Inhibitors of ACC can reduce fatty acid synthesis and increase fatty acid oxidation, potentially ameliorating the lipid imbalances associated with these conditions.

Research

Research into ACC is ongoing, with studies focusing on understanding its structure-function relationships, regulatory mechanisms, and its role in disease. Novel ACC inhibitors are being developed and tested for their therapeutic potential in metabolic diseases.