AACS - Acetoacetyl-CoA Synthetase | Elisa - Clia - Antibody - Protein

Background

Acetoacetyl-CoA synthetase (AACS) is an enzyme that plays an important role in cellular metabolism, specifically in the ketone body metabolism and fatty acid synthesis pathways. AACS catalyzes the formation of acetoacetyl-CoA from acetoacetate and CoA (coenzyme A), which is a crucial intermediate in the metabolism of ketone bodies and fatty acids.

The enzyme is involved in the reversible conversion between acetoacetate (one of the three primary ketone bodies produced in the liver during periods of fasting, prolonged exercise, or carbohydrate restriction) and acetoacetyl-CoA, a precursor for both cholesterol synthesis and the synthesis of long-chain fatty acids. AACS is found primarily in the cytoplasm and mitochondria of various tissues, including the liver, heart, and skeletal muscle, where it plays a role in regulating energy metabolism.

The enzyme’s activity is significant in conditions of ketosis, when the body uses fat as a primary energy source, such as during fasting, prolonged exercise, or low-carbohydrate diets. By regulating the formation and utilization of acetoacetyl-CoA, AACS helps maintain energy balance and ensures efficient use of fatty acids and ketone bodies as fuel sources.

Protein Structure

Acetoacetyl-CoA synthetase (AACS) is a member of the CoA ligase family, a group of enzymes that activate fatty acids, ketone bodies, and other metabolites by attaching coenzyme A (CoA) to form thioester bonds. The structural features of AACS facilitate its enzymatic activity in the conversion of acetoacetate to acetoacetyl-CoA. Some key features of its structure include:

1. ATP-Binding Domain: AACS, like other enzymes in the CoA ligase family, contains an ATP-binding domain that is responsible for hydrolyzing ATP to provide the energy required for the activation of the acetoacetate molecule. This domain facilitates the attachment of CoA to acetoacetate to form acetoacetyl-CoA.
2. Acetoacetate Binding Site: AACS has a binding site that specifically recognizes acetoacetate and CoA, two substrates necessary for its catalytic activity. This site is designed to stabilize acetoacetate and facilitate its interaction with ATP and CoA during the reaction.
3. CoA Binding Site: The enzyme also contains a binding site for CoA, which is essential for the formation of the acetoacetyl-CoA product. This site ensures that the enzyme can efficiently catalyze the transfer of the CoA group to acetoacetate.
4. Conformational Flexibility: Like many enzymes, AACS undergoes conformational changes during catalysis. The binding of substrates such as acetoacetate and CoA triggers the formation of the enzyme-substrate complex, which then facilitates the transfer of CoA and ATP hydrolysis, ultimately generating acetoacetyl-CoA.
5. Dimeric or Tetrameric Structure: AACS functions as a dimer or tetramer depending on the tissue type and cellular conditions. The oligomeric state contributes to its stability and functional efficiency in various metabolic contexts.

These structural elements ensure that AACS can efficiently catalyze the conversion of acetoacetate to acetoacetyl-CoA, a vital step in energy metabolism.

Classification and Subtypes

AACS is classified as a CoA ligase, a subgroup of enzymes involved in the activation of fatty acids, ketone bodies, and other metabolites by attaching CoA groups. CoA ligases are classified into several families based on the substrates they act on and the specific metabolic pathways they participate in. AACS belongs to the short-chain acyl-CoA synthetase (SCAS) family, which includes enzymes that act on short-chain fatty acids, ketone bodies, and other metabolites.

While AACS does not have well-defined subtypes, there are other related CoA ligases involved in similar metabolic processes:

1. Acyl-CoA synthetases: These enzymes catalyze the activation of fatty acids by attaching CoA groups, forming acyl-CoA derivatives that are critical intermediates in lipid metabolism.
2. Ketone body metabolism enzymes: AACS is involved in ketone body utilization, and other enzymes like β-hydroxybutyrate dehydrogenase and acetoacetate decarboxylase work in concert with AACS in the utilization of ketone bodies for energy.

Although there are no distinct subtypes of AACS itself, the enzyme is closely related to other members of the CoA ligase family that facilitate the activation of metabolites involved in energy metabolism.

Function and Biological Significance

AACS plays an essential role in ketone body metabolism and lipid metabolism, and its activity is critical for maintaining energy balance, particularly in energy-demanding tissues like the liver, heart, and skeletal muscle. The enzyme’s functions include:

1. Ketone Body Metabolism: During periods of fasting, prolonged exercise, or carbohydrate restriction, the liver produces ketone bodies (acetone, acetoacetate, and β-hydroxybutyrate) as an alternative energy source to glucose. AACS catalyzes the conversion of acetoacetate (one of the primary ketone bodies) into acetoacetyl-CoA, which can then enter various metabolic pathways, including the Krebs cycle and fatty acid synthesis. This conversion enables tissues to utilize ketone bodies as an energy source.
2. Fatty Acid Synthesis: Acetoacetyl-CoA, produced by AACS, is an important intermediate in fatty acid synthesis and cholesterol biosynthesis. Acetoacetyl-CoA can be used to form malonyl-CoA, which is a precursor for fatty acid biosynthesis. Additionally, it is involved in the synthesis of cholesterol, an essential lipid for membrane structure and steroid hormone production.
3. Regulation of Energy Homeostasis: AACS plays a vital role in energy homeostasis, particularly during periods of low glucose availability. It helps regulate the balance between glucose and fatty acid metabolism by facilitating the use of ketone bodies as an alternative fuel. This regulation is crucial during fasting, starvation, or carbohydrate-restricted states, as it ensures that energy needs are met through efficient use of fatty acids and ketones.
4. Neuroprotective Role: Acetoacetyl-CoA, produced by AACS, can be utilized in neurons for energy production, especially during ketosis, when glucose is less available. The brain can use ketone bodies as an alternative energy source, which is particularly important during prolonged fasting or in ketogenic states. This process supports neuroprotection and cognitive function in energy-limited conditions.
5. Regulation of Fatty Acid and Lipid Metabolism: AACS also participates in regulating the conversion of fatty acids into lipid intermediates. Acetoacetyl-CoA is a key metabolite in both lipogenesis and lipid oxidation, balancing the synthesis and breakdown of lipids for energy production and storage.

Clinical Issues

Given its central role in ketone body and lipid metabolism, AACS is associated with several clinical conditions:

1. Ketone Body Disorders: Deficiencies in enzymes involved in ketone body metabolism, including AACS, can lead to disorders where the body cannot efficiently produce or utilize ketones for energy. This can result in hypoglycemia and energy deficits during periods of fasting or carbohydrate restriction, potentially leading to neurological dysfunction and organ damage in severe cases.
2. Fatty Acid Metabolism Disorders: Since AACS is involved in fatty acid and cholesterol metabolism, any dysfunction in the enzyme’s activity can lead to disorders related to lipid metabolism, such as dyslipidemia, obesity, and metabolic syndrome. Impaired conversion of acetoacetate to acetoacetyl-CoA may disrupt the synthesis of essential lipids, contributing to lipid accumulation and cardiovascular disease.
3. Neurological Conditions: As AACS plays a role in supplying neuroprotective ketone bodies to the brain during fasting or low glucose states, defects in AACS activity could contribute to neurological disorders. Reduced availability of ketone bodies in the brain may impair cognitive function, especially in individuals with Alzheimer’s disease, Parkinson’s disease, or other neurodegenerative disorders that rely on alternative energy substrates like ketones.
4. Cancer: Alterations in ketone body and fatty acid metabolism, including the activity of enzymes like AACS, may also be linked to cancer metabolism. Some cancer cells alter their metabolic pathways to utilize ketone bodies and fatty acids for energy and biosynthesis. Understanding AACS’s role in these pathways may provide insights into cancer cell metabolism and potential therapeutic targets.

Summary

1. Acetoacetyl-CoA synthetase (AACS) is an essential enzyme in ketone body metabolism and lipid metabolism, responsible for converting acetoacetate into acetoacetyl-CoA, a key intermediate in fatty acid synthesis and cholesterol biosynthesis. AACS regulates the balance between glucose and fatty acid metabolism, especially during periods of fasting or low carbohydrate availability, by facilitating the use of ketone bodies as an alternative energy source. The enzyme’s role is crucial in maintaining energy homeostasis, neuroprotection, and lipid synthesis. Dysregulation of AACS can lead to metabolic disorders, including ketone body disorders, fatty acid metabolism disorders, and neurological conditions. Understanding AACS's functions and its role in metabolic regulation offers insights into potential therapeutic strategies for diseases related to energy metabolism and neurodegeneration.