ACAA - Acetyl Coenzyme A Acyltransferase | Elisa - Clia - Antibody - Protein

Background

Acetyl Coenzyme A Acyltransferase (ACAA) is an enzyme involved in lipid metabolism, specifically in the β-oxidation pathway of fatty acids. ACAA catalyzes the final step in this pathway, facilitating the thiolytic cleavage of 3-ketoacyl-CoA into acetyl-CoA and a shorter acyl-CoA molecule. This process is critical for energy production, particularly in tissues that rely heavily on fatty acid oxidation, such as the liver and muscles.There are several isoforms of Acetyl-CoA Acyltransferase, including ACAA1, ACAA2, ACAA1A, and ACAA1B, each encoded by different genes and localized to different cellular compartments. ACAA1: This isoform is typically found in peroxisomes, which are cellular organelles involved in lipid metabolism. It plays a significant role in the breakdown of long-chain fatty acids. ACAA2: This isoform is primarily located in mitochondria, another cellular organelle where beta-oxidation of fatty acids occurs. ACAA2 is involved in the metabolism of short and medium-chain fatty acids. ACAA1A and ACAA1B: These isoforms are subtypes of ACAA1, and they share similar functions with ACAA1 in peroxisomal fatty acid oxidation. Mutations in genes encoding ACAA isoforms can lead to metabolic disorders known as peroxisomal disorders or defects in fatty acid oxidation, which can have severe consequences for health.

Protein Structure

ACAA proteins have distinct structural features that enable their enzymatic activity:

• Catalytic Domain: This domain is responsible for the thiolase activity, catalyzing the thiolytic cleavage of 3-ketoacyl-CoA substrates.
• Binding Sites: Specific sites on the enzyme bind to Coenzyme A and the 3-ketoacyl substrates, facilitating the catalytic process.
• Dimerization Interface: ACAA typically functions as a homodimer, and the interface between the two monomers is crucial for its enzymatic activity and stability.

Classification and Subtypes

The ACAA family includes two main subtypes based on their subcellular localization and function:

• ACAA1 (Peroxisomal 3-Ketoacyl-CoA Thiolase): Located in the peroxisomes, ACAA1 is involved in the peroxisomal β-oxidation pathway, which handles very long-chain and branched-chain fatty acids.
• ACAA2 (Mitochondrial 3-Ketoacyl-CoA Thiolase): Found in the mitochondria, ACAA2 participates in the mitochondrial β-oxidation pathway, which processes medium- to long-chain fatty acids.

Function and Biological Significance

ACAA enzymes play crucial roles in lipid metabolism:

1. Energy Production: By catalyzing the thiolytic cleavage of 3-ketoacyl-CoA, ACAA enzymes generate acetyl-CoA, which enters the citric acid cycle for ATP production.
2. Fatty Acid Degradation: ACAA enzymes are essential for the degradation of fatty acids, providing an energy source during fasting or extended periods of exercise.
3. Ketogenesis: In the liver, acetyl-CoA produced by ACAA activity can be used for ketogenesis, forming ketone bodies that serve as alternative energy sources for peripheral tissues, including the brain during starvation.

Interactions

ACAA enzymes interact with various molecules and proteins:

1. Coenzyme A (CoA): ACAA enzymes bind CoA derivatives, facilitating the thiolysis of 3-ketoacyl-CoA substrates.
2. Fatty Acid Metabolizing Enzymes: They work in concert with other enzymes in the β-oxidation pathway, such as acyl-CoA dehydrogenase and enoyl-CoA hydratase.
3. Transport Proteins: Peroxisomal and mitochondrial transport proteins ensure the delivery of substrates and products to and from ACAA enzymes, coordinating metabolic processes.

Clinical Significance

Dysfunction of ACAA enzymes can lead to metabolic disorders:

1. ACAA1 Deficiency: Mutations in the ACAA1 gene can lead to peroxisomal disorders, such as D-bifunctional protein deficiency, characterized by the accumulation of very long-chain fatty acids and neurological impairment.
2. ACAA2 Deficiency: Mutations in the ACAA2 gene can cause mitochondrial β-oxidation disorders, resulting in muscle weakness, cardiomyopathy, hypoglycemia, and metabolic crises during periods of fasting or illness.
3. Metabolic Syndrome: Impaired fatty acid oxidation, potentially involving ACAA dysfunction, can contribute to the development of obesity, insulin resistance, and type 2 diabetes.

Summary

Acetyl Coenzyme A Acyltransferase (ACAA) is essential for lipid metabolism, specifically in the β-oxidation pathway of fatty acids. The two main subtypes, ACAA1 and ACAA2, are localized in the peroxisomes and mitochondria, respectively, and play critical roles in energy production, fatty acid degradation, and ketogenesis. Interacting with CoA derivatives and other fatty acid metabolizing enzymes, ACAA enzymes ensure efficient lipid metabolism. Dysregulation or mutations in ACAA enzymes can lead to metabolic disorders, highlighting their importance in maintaining metabolic homeostasis.