ACLY - ATP-Citrate Synthase | Elisa - Clia - Antibody - Protein

Background

ATP-citrate lyase (ACLY) is an essential enzyme in cellular metabolism, playing a pivotal role in the conversion of citrate into acetyl-CoA and oxaloacetate. ACLY-ATP-Citrate Synthase refers to a crucial metabolic pathway involved in cellular energy production and lipid synthesis. ACLY, or ATP-citrate lyase, is an enzyme that catalyzes the conversion of citrate from mitochondria-derived oxaloacetate and acetyl-CoA from the cytoplasm. This reaction produces cytoplasmic citrate, which serves as a substrate for lipid biosynthesis. ATP, or adenosine triphosphate, provides the necessary energy for ACLY to carry out this reaction. Subsequently, citrate is cleaved by ATP-citrate synthase, releasing acetyl-CoA for fatty acid synthesis and providing the building blocks for lipid molecules essential for cellular membranes and energy storage. This pathway is particularly active in lipogenic tissues like the liver and adipose tissue, where it plays a critical role in regulating lipid metabolism and energy homeostasis. Dysregulation of ACLY-ATP-citrate synthase pathway has been implicated in various metabolic disorders, including obesity, diabetes, and cancer. Understanding the molecular mechanisms underlying this pathway offers potential therapeutic targets for metabolic diseases. Ongoing research aims to elucidate the intricate regulation and significance of ACLY-ATP-citrate synthase in cellular metabolism and disease pathogenesis.

Protein Structure

ACLY is a homotetramer composed of identical subunits, each with distinct functional domains:

• N-terminal Citrate Binding Domain: This domain binds citrate, the substrate for the enzymatic reaction.
• ATP-Grasp Domain: Responsible for ATP binding and hydrolysis, necessary for the cleavage of citrate.
• CoA Binding Domain: Binds coenzyme A (CoA), facilitating the transfer of the acetyl group.
• Catalytic Core: Contains the active site where the conversion of citrate to acetyl-CoA and oxaloacetate occurs.

Classification and Subtypes

ACLY belongs to the ATP-citrate lyase family of enzymes. While there is only one main isoform of ACLY in humans, variations in its regulation and activity can occur due to alternative splicing, post-translational modifications, and interaction with other proteins.

Function and Biological Significance

ACLY serves several vital functions in cellular metabolism:

1. Acetyl-CoA Production: ACLY catalyzes the production of acetyl-CoA from citrate, a crucial metabolite for fatty acid and cholesterol synthesis.
2. Lipid Biosynthesis: Acetyl-CoA generated by ACLY is a substrate for the synthesis of fatty acids and cholesterol, essential for cell membrane formation and energy storage.
3. Energy Homeostasis: By linking glycolysis and lipid synthesis, ACLY plays a significant role in maintaining cellular energy balance.
4. Gene Regulation: Acetyl-CoA produced by ACLY is used for histone acetylation, a process that regulates gene expression by modifying chromatin structure.
5. Metabolic Adaptation: ACLY activity is upregulated in rapidly proliferating cells, such as cancer cells, to meet the increased demand for acetyl-CoA and lipids.

Interactions

ACLY interacts with various proteins and molecules to execute its functions:

1. Citrate: The primary substrate for ACLY, derived from the citric acid cycle.
2. Coenzyme A (CoA): Essential for the transfer of the acetyl group, forming acetyl-CoA.
3. ATP: Provides the energy required for the enzymatic reaction, binding to the ATP-grasp domain.
4. Protein Kinases: ACLY is regulated by phosphorylation through kinases such as AMP-activated protein kinase (AMPK) and Akt, which modulate its activity in response to cellular energy levels and growth signals.
5. Histone Acetyltransferases: Utilize acetyl-CoA produced by ACLY for histone acetylation, impacting gene expression.

Clinical Significance

Alterations in ACLY function and regulation are implicated in various diseases:

1. Metabolic Disorders: Dysregulation of ACLY activity can contribute to obesity, insulin resistance, and type 2 diabetes by affecting lipid synthesis and storage.
2. Cancer: ACLY is often upregulated in cancer cells, providing acetyl-CoA for lipid biosynthesis and histone acetylation, supporting rapid cell proliferation and tumor growth. Inhibitors of ACLY are being explored as potential cancer therapies.
3. Cardiovascular Disease: Enhanced ACLY activity can lead to increased cholesterol synthesis, contributing to the development of atherosclerosis and cardiovascular disease.
4. Neurodegenerative Diseases: Altered ACLY activity may impact neuronal lipid metabolism and gene expression, influencing the pathogenesis of neurodegenerative conditions like Alzheimer's disease.

Summary

ATP-citrate lyase (ACLY) is a critical enzyme that catalyzes the conversion of citrate to acetyl-CoA and oxaloacetate, linking carbohydrate metabolism to lipid biosynthesis. ACLY plays essential roles in acetyl-CoA production, lipid biosynthesis, energy homeostasis, gene regulation, and metabolic adaptation. Dysregulation of ACLY activity is associated with various diseases, including metabolic disorders, cancer, cardiovascular disease, and neurodegenerative conditions. Understanding the structure, function, interactions, and clinical significance of ACLY provides valuable insights into its role in health and disease and highlights its potential as a therapeutic target.