ACSS - Acyl-CoA Synthetase Short-Chain Family Member | Elisa - Clia - Antibody - Protein

Background

Acyl-CoA Synthetase Short-Chain (ACSS) family members are enzymes responsible for activating short-chain fatty acids (SCFAs), typically those with fewer than six carbon atoms. Similar to the ACSM family, ACSS enzymes catalyze the conversion of short-chain fatty acids into acyl-CoA thioesters. This activation step is crucial for the utilization of these fatty acids in various metabolic processes, including energy production through β-oxidation or incorporation into lipid biosynthesis pathways. Production of acetyl-CoA is related to histone acetylation and gene regulation. Acetyl-CoA Synthetase 2 (ACSS2) is highly expressed in a variety of tumors, which is very important for tumor growth, proliferation and metastasis .It has been also shown that ACSS2 inhibitors can be effective in halting cancer growth and can be combined with other antineoplastic drugs to reduce drug resistance. ACSS2, which has been extensively studied due to its involvement in cellular metabolism and its potential role in cancer progression. ACSS2 has been shown to play a critical role in providing acetyl-CoA for lipid synthesis in cancer cells, particularly under conditions of glucose deprivation. This highlights the importance of ACSS enzymes in cellular energy metabolism and suggests their potential as therapeutic targets in cancer and metabolic diseases.

Protein Structure

The structure of ACSS enzymes includes several key domains and motifs:

• ATP Binding Domain: Critical for binding and hydrolyzing ATP, providing the energy necessary for the activation of fatty acids.
• Fatty Acid Binding Site: Regions that specifically bind to short-chain fatty acids, positioning them for activation.
• Catalytic Core: Contains key residues involved in the formation of acyl-CoA from fatty acids and Coenzyme A (CoA).

Classification and Subtypes

The ACSS family is classified based on substrate specificity and tissue distribution. Key members include:

• ACSS1: Primarily involved in the metabolism of short-chain fatty acids, particularly acetate, and expressed in mitochondria.
• ACSS2: Catalyzes the activation of acetate and other short-chain fatty acids, mainly found in the cytoplasm.
• ACSS3: Plays a role in short-chain fatty acid metabolism, with specific tissue distributions and functions.

Function and Biological Significance

ACSS enzymes serve essential functions in various metabolic processes:

1. Fatty Acid Activation: Catalyze the conversion of short-chain fatty acids into acyl-CoA derivatives, a critical step for their subsequent metabolism.
2. Energy Production: Facilitate the breakdown of short-chain fatty acids via β-oxidation, contributing to ATP production.
3. Lipid Biosynthesis: Participate in the synthesis of complex lipids, such as triglycerides and phospholipids, for membrane formation and storage.
4. Metabolic Regulation: Regulate the availability of acyl-CoA derivatives, influencing various metabolic pathways and energy homeostasis.
5. Acetate Metabolism: Involved in the conversion of acetate to acetyl-CoA, a key substrate for the citric acid cycle and lipid biosynthesis.

Interactions

ACSS enzymes interact with various molecules and metabolic pathways:

1. Coenzyme A (CoA): A crucial co-substrate in the formation of acyl-CoA.
2. ATP: Provides the energy required for the activation of fatty acids.
3. Fatty Acid β-Oxidation Pathway: Interact with enzymes involved in the breakdown of short-chain fatty acids for energy production.
4. Lipid Biosynthesis Pathways: Engage with enzymes and substrates involved in the synthesis of complex lipids.
5. Citric Acid Cycle: ACSS enzymes, particularly ACSS2, are involved in the provision of acetyl-CoA for the citric acid cycle.

Clinical Significance

Alterations or deficiencies in ACSS enzymes can lead to several metabolic disorders:

1. Inherited Metabolic Disorders: Mutations in ACSS genes can result in specific metabolic syndromes characterized by abnormal fatty acid metabolism.
2. Energy Metabolism Disorders: Impaired function of ACSS enzymes can disrupt normal fatty acid catabolism, leading to energy production deficiencies and related metabolic diseases.
3. Lipid Storage Disorders: Dysregulation of ACSS activity can affect lipid biosynthesis and storage, contributing to conditions such as fatty liver disease and obesity.
4. Cancer Metabolism: ACSS2, in particular, has been implicated in cancer metabolism, where cancer cells utilize acetate as an alternative energy source.
5. Potential Therapeutic Targets: Given their central role in lipid and energy metabolism, ACSS enzymes are potential targets for therapeutic interventions in metabolic diseases and conditions such as cardiovascular disease and cancer.

Summary

The Acyl-CoA Synthetase Short-Chain (ACSS) family includes enzymes essential for the activation of short-chain fatty acids by converting them into acyl-CoA derivatives. This activation is crucial for fatty acid metabolism, including degradation, lipid biosynthesis, and energy production. Key members such as ACSS1, ACSS2, and ACSS3 each have specific roles and tissue distributions. Dysfunctions or mutations in these enzymes can lead to various metabolic disorders, emphasizing their importance in maintaining lipid homeostasis and energy balance. Understanding the structure, function, interactions, and clinical implications of ACSS enzymes provides valuable insights into their roles in metabolic processes and potential therapeutic applications.