ACAC - Acetyl Coenzyme A Carboxylase Alpha/Beta | Elisa - Clia - Antibody - Protein

Background

Acetyl Coenzyme A Carboxylase (ACAC) is a crucial enzyme in fatty acid metabolism, playing a key role in the regulation of fatty acid synthesis. It catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the first committed step in fatty acid biosynthesis. ACACA (Alpha), also known as ACC1, is primarily found in the cytoplasm. It plays a central role in lipogenesis (the synthesis of fatty acids) by producing malonyl-CoA, which serves as a precursor for fatty acid synthesis and as an inhibitor of fatty acid oxidation. ACACB (Beta), also known as ACC2, is primarily located in mitochondria, where it regulates fatty acid oxidation. Unlike ACACA, which generates malonyl-CoA in the cytoplasm for fatty acid synthesis, ACACB produces malonyl-CoA in mitochondria, where it acts as an allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT1). CPT1 is a key enzyme involved in the transport of fatty acids into the mitochondria for oxidation. By inhibiting CPT1, ACACB helps to regulate fatty acid oxidation based on cellular energy needs. Both isoforms of Acetyl-CoA Carboxylase are subject to complex regulation at multiple levels, including transcriptional, post-translational, and allosteric regulation, to ensure that fatty acid synthesis and oxidation are coordinated according to cellular energy demands and nutritional status.

Protein Structure

Both ACACA and ACACB share common structural features essential for their function:

• Biotin Carboxylase Domain: Catalyzes the ATP-dependent carboxylation of biotin.
• Biotin Carboxyl Carrier Protein (BCCP) Domain: Carries the biotin prosthetic group that is carboxylated and then transferred to acetyl-CoA.
• Carboxyltransferase Domain: Transfers the carboxyl group from biotin to acetyl-CoA, forming malonyl-CoA.
• Regulatory Domains: Various regulatory motifs allow the enzyme to be controlled by phosphorylation, allosteric effectors, and interactions with other proteins.

Classification and Subtypes

ACAC enzymes are classified into two main isoforms:

• ACACA (Alpha): Predominantly found in lipogenic tissues such as liver, adipose tissue, and mammary glands. It is primarily involved in de novo fatty acid synthesis.
• ACACB (Beta): Mainly expressed in oxidative tissues such as muscle and heart. It regulates the rate of fatty acid oxidation by controlling the levels of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 (CPT1), which is crucial for fatty acid transport into mitochondria for oxidation.

Function and Biological Significance

ACAC enzymes have pivotal roles in lipid metabolism:

1. Fatty Acid Synthesis: ACACA catalyzes the formation of malonyl-CoA, which is a key precursor in the elongation of fatty acid chains during de novo fatty acid synthesis.
2. Regulation of Fatty Acid Oxidation: ACACB modulates the levels of malonyl-CoA in muscle and heart tissues, thereby regulating fatty acid oxidation by inhibiting CPT1.
3. Metabolic Regulation: Both isoforms of ACAC are key regulators of lipid homeostasis, balancing the synthesis and degradation of fatty acids according to cellular energy status.

Interactions

ACAC enzymes interact with various molecules and proteins:

1. Citrate: Acts as an allosteric activator of ACAC, enhancing its activity when fatty acid synthesis is needed.
2. AMP-Activated Protein Kinase (AMPK): Phosphorylates and inhibits ACAC in response to low energy status, decreasing fatty acid synthesis and increasing fatty acid oxidation.
3. Insulin and Glucagon: Hormonal signals that regulate ACAC activity, with insulin promoting and glucagon inhibiting ACAC activity, thus coordinating lipid metabolism with overall energy status.

Clinical Significance

Dysregulation of ACAC enzymes is associated with several metabolic diseases:

1. Obesity and Insulin Resistance: Overactivity of ACACA can lead to excessive fatty acid synthesis and storage, contributing to obesity and insulin resistance.
2. Diabetes: Dysregulated ACAC activity can affect lipid metabolism and glucose homeostasis, playing a role in the pathogenesis of type 2 diabetes.
3. Cardiovascular Diseases: Imbalanced fatty acid synthesis and oxidation due to ACAC dysfunction can contribute to the development of cardiovascular diseases by promoting lipid accumulation and inflammation.
4. Cancer: Increased expression and activity of ACACA have been observed in various cancers, where enhanced fatty acid synthesis supports rapid cell proliferation and tumor growth.

Summary

Acetyl Coenzyme A Carboxylase (ACAC) is a key enzyme in fatty acid metabolism, with two main isoforms, ACACA and ACACB, that regulate fatty acid synthesis and oxidation. These enzymes catalyze the formation of malonyl-CoA, a crucial metabolite in lipid metabolism. ACAC enzymes are regulated by nutritional and hormonal signals, ensuring proper lipid homeostasis. Dysregulation of ACAC activity is implicated in metabolic disorders such as obesity, diabetes, cardiovascular diseases, and cancer, highlighting their importance in maintaining metabolic balance and health.