Acetyl-CoA carboxylase, often abbreviated as ACC, is an enzyme that functions within the cells of most living organisms. It plays a part in a fundamental metabolic process: the conversion of acetyl-CoA, a molecule derived from the breakdown of carbohydrates, into a compound that serves as a primary building block for creating fatty acids. This role places ACC at a metabolic crossroads, influencing how cells manage their energy resources. Essentially, it helps direct building blocks from dietary carbohydrates toward the synthesis of fats, which are a principal form of long-term energy storage.
The Catalytic Reaction of Acetyl-CoA Carboxylase
Acetyl-CoA carboxylase (ACC) performs a specific chemical transformation: it attaches a carboxyl group to an acetyl-CoA molecule. This reaction, known as carboxylation, converts acetyl-CoA into a new molecule called malonyl-CoA. For this to occur, the enzyme requires several key inputs. The first is acetyl-CoA itself, which provides the foundational two-carbon structure, and the second is bicarbonate, which serves as the source of the carboxyl group being added.
The energy needed to drive this reaction is supplied by adenosine triphosphate (ATP), the cell’s main energy currency. The process also depends on a cofactor, the vitamin biotin. Biotin is covalently attached to the enzyme and acts as a temporary carrier, first picking up the carboxyl group from bicarbonate and then transferring it onto acetyl-CoA. The reaction happens in two distinct steps at different active sites on the enzyme: first, the biotin is carboxylated, and second, the carboxyl group is transferred to acetyl-CoA, finalizing the creation of malonyl-CoA.
The Committed Step in Fatty Acid Creation
The conversion of acetyl-CoA to malonyl-CoA by ACC is significant because it represents the first committed step in the pathway of de novo fatty acid synthesis, the process of building fatty acids from scratch. Malonyl-CoA is the primary building block used by another enzyme complex, fatty acid synthase, to construct long chains of fatty acids. Once acetyl-CoA is converted to malonyl-CoA, it is effectively earmarked for this purpose and is unlikely to be used in other metabolic pathways.
This reaction is also the rate-limiting step of the entire fatty acid synthesis process. This means the speed at which ACC can produce malonyl-CoA dictates the overall rate at which a cell can generate new fatty acids. This characteristic makes ACC a major control point for regulating the amount of fat a cell produces and stores, ensuring that this energy-intensive process is tightly managed based on the cell’s metabolic state.
How Enzyme Activity is Regulated
The activity of Acetyl-CoA carboxylase is controlled through multiple mechanisms to match the cell’s energy needs. One level of control is allosteric regulation, where molecules bind to the enzyme at a site other than the active site to change its activity. Citrate, a molecule that accumulates when there is an abundance of acetyl-CoA and ATP, acts as a potent activator. Its presence signals that the cell has ample energy and building blocks, promoting ACC to polymerize into long, active filaments and ramp up malonyl-CoA production for fat storage. Conversely, long-chain fatty acyl-CoAs, the end products of fatty acid synthesis, act as feedback inhibitors, signaling that enough fat has been made.
A second layer of regulation comes from hormones, which communicate the body’s overall energy status. When blood sugar is high, the hormone insulin is released, which triggers a phosphatase enzyme to dephosphorylate ACC, activating it. In contrast, during periods of low energy, hormones like glucagon and epinephrine initiate a signaling cascade that leads to the phosphorylation of ACC by AMP-activated protein kinase (AMPK). This phosphorylation inactivates the enzyme, preventing it from producing malonyl-CoA and thus halting fatty acid synthesis to conserve energy.
Different Forms and Functions of the Enzyme
In mammals, Acetyl-CoA carboxylase exists in two primary forms, or isoforms, known as ACC1 and ACC2. These isoforms are encoded by different genes and, while they perform the same basic chemical reaction, their distinct locations within the cell lead to different physiological roles. ACC1 is predominantly found in the cytoplasm of cells in lipogenic tissues, such as the liver and adipose tissue. Its main function is to produce the malonyl-CoA that serves as the substrate for fatty acid synthase, directly contributing to the synthesis of new fatty acids.
ACC2, on the other hand, is uniquely located on the outer membrane of mitochondria, the cell’s powerhouses. The malonyl-CoA produced by ACC2 has a specific regulatory function. It inhibits an enzyme called carnitine palmitoyltransferase 1 (CPT1), which is responsible for transporting fatty acids into the mitochondria to be broken down for energy in a process called beta-oxidation. By inhibiting CPT1, the malonyl-CoA generated by ACC2 effectively acts as a brake on fatty acid breakdown, ensuring that synthesis and degradation of fats do not occur simultaneously.
Relevance in Metabolism and Disease
The regulation of Acetyl-CoA carboxylase is closely linked to metabolic health, and its dysregulation is implicated in several common diseases. In conditions like obesity and type 2 diabetes, ACC activity is often inappropriately high. This leads to excessive de novo fatty acid synthesis, contributing to the accumulation of fat in the liver (non-alcoholic fatty liver disease) and adipose tissue, and can worsen insulin resistance.
Furthermore, many types of cancer cells display a heightened reliance on fatty acid synthesis to support their rapid growth and proliferation. These cells often show increased ACC1 activity to produce the lipids required for building new cell membranes. This dependency has made ACC a significant area of interest for drug development. Researchers are actively developing inhibitors that target ACC with the goal of creating new therapeutic strategies for treating metabolic disorders and certain types of cancer by controlling the synthesis of fatty acids.