ACAD - Acyl-CoA Dehydrogenase | Elisa - Clia - Antibody - Protein

Background

Acyl-CoA dehydrogenases (ACADs) are a family of enzymes involved in the β-oxidation of fatty acids. These enzymes catalyze the first step in the mitochondrial fatty acid β-oxidation pathway, which involves the dehydrogenation of acyl-CoA thioesters. This reaction is crucial for the breakdown of fatty acids into acetyl-CoA units, which can then enter the citric acid cycle to produce ATP, providing energy for the cell.This process occurs within the mitochondria of cells and is essential for generating energy from fatty acids. Mutations in the genes encoding acyl-CoA dehydrogenase can lead to various metabolic disorders known as fatty acid oxidation disorders (FAODs). These disorders can cause symptoms such as hypoglycemia, muscle weakness, and even life-threatening metabolic crises. Early detection through newborn screening and dietary management are crucial for managing FAODs. Acyl-CoA dehydrogenase deficiency is categorized into different types depending on the specific enzyme affected, such as short-chain, medium-chain, and long-chain acyl-CoA dehydrogenase deficiencies. Treatment often involves a combination of dietary interventions, supplements, and medications to manage symptoms and prevent metabolic crises. Understanding the function of acyl-CoA dehydrogenase is vital for developing targeted therapies for FAODs and improving patient outcomes. Ongoing research continues to uncover the intricate role of this enzyme in cellular metabolism and its implications for human health.

Protein Structure

ACAD enzymes share common structural features:

• FAD Binding Domain: ACAD enzymes bind flavin adenine dinucleotide (FAD), a cofactor essential for their dehydrogenase activity.
• Catalytic Domain: This domain contains the active site where the dehydrogenation reaction occurs, converting acyl-CoA substrates to 2-enoyl-CoA.
• Substrate Binding Sites: Specific sites on the enzyme bind to different chain-length acyl-CoA substrates, determining the enzyme’s substrate specificity.

Classification and Subtypes

The ACAD family includes several members, each with specificity for different chain-length fatty acids:

• ACADM (Medium-chain Acyl-CoA Dehydrogenase): Catalyzes the dehydrogenation of medium-chain fatty acids (C4-C12).
• ACADL (Long-chain Acyl-CoA Dehydrogenase): Catalyzes the dehydrogenation of long-chain fatty acids (C12-C16).
• ACADVL (Very Long-chain Acyl-CoA Dehydrogenase): Catalyzes the dehydrogenation of very long-chain fatty acids (C14-C20).
• ACADS (Short-chain Acyl-CoA Dehydrogenase): Catalyzes the dehydrogenation of short-chain fatty acids (C2-C4).
• ACAD9: Involved in the dehydrogenation of long-chain fatty acids and has additional roles in mitochondrial function and maintenance.

The genes Acad8, Acad9, Acad10, and Acad11 are associated with various types of acyl-CoA dehydrogenase deficiencies, which are metabolic disorders affecting the body's ability to break down certain fatty acids. These deficiencies are linked to different types of fatty acid oxidation disorders, namely MCADD, LCHADD, SCADD, and VLCADD. Here's a breakdown of the relationship between these genes and the corresponding disorders:

1. MCADD (Medium-Chain Acyl-CoA Dehydrogenase Deficiency):

• Gene: ACADM (Acad8)
• Description: This condition is caused by mutations in the ACADM gene, leading to a deficiency in the medium-chain acyl-CoA dehydrogenase enzyme. This enzyme is crucial for the breakdown of medium-chain fatty acids.

2. LCHADD (Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency):

• Gene: HADHA (Acad9)
• Description: Mutations in the HADHA gene result in a deficiency of the long-chain 3-hydroxyacyl-CoA dehydrogenase enzyme, affecting the metabolism of long-chain fatty acids.

3. SCADD (Short-Chain Acyl-CoA Dehydrogenase Deficiency):

• Gene: ACADS (Acad10)
• Description: This disorder is caused by mutations in the ACADS gene, leading to a deficiency in short-chain acyl-CoA dehydrogenase, which is involved in the metabolism of short-chain fatty acids.

4. VLCADD (Very Long-Chain Acyl-CoA Dehydrogenase Deficiency):

• Gene: ACADVL (Acad11)
• Description: Mutations in the ACADVL gene cause a deficiency in the very long-chain acyl-CoA dehydrogenase enzyme, affecting the breakdown of very long-chain fatty acids.

Function and Biological Significance

ACAD enzymes play critical roles in cellular metabolism:

1. Energy Production: By catalyzing the dehydrogenation of acyl-CoA, ACAD enzymes initiate the β-oxidation pathway, leading to the production of acetyl-CoA and ATP.
2. Fatty Acid Degradation: ACAD enzymes are essential for the breakdown of dietary and stored fatty acids, particularly during periods of fasting or increased energy demand.
3. Metabolic Regulation: By regulating the levels of acyl-CoA and acetyl-CoA, ACAD enzymes influence various metabolic pathways, including the citric acid cycle and ketogenesis.

Interactions

ACAD enzymes interact with various molecules and proteins:

1. Flavin Adenine Dinucleotide (FAD): Acts as a cofactor, accepting electrons during the dehydrogenation reaction.
2. Electron Transfer Flavoprotein (ETF): Transfers electrons from ACAD enzymes to the mitochondrial respiratory chain, linking β-oxidation to ATP production.
3. Acyl-CoA Substrates: Specific binding sites on ACAD enzymes interact with acyl-CoA substrates of varying chain lengths, determining enzyme specificity.

Clinical Significance

Deficiencies in ACAD enzymes can lead to metabolic disorders:

1. Medium-chain Acyl-CoA Dehydrogenase Deficiency (MCADD): Caused by mutations in the ACADM gene, leading to impaired oxidation of medium-chain fatty acids. Symptoms include hypoglycemia, lethargy, and potentially life-threatening metabolic crises.
2. Long-chain Acyl-CoA Dehydrogenase Deficiency (LCADD): Due to mutations in the ACADL gene, resulting in the accumulation of long-chain fatty acids and associated with cardiomyopathy, muscle weakness, and hypoglycemia.
3. Very Long-chain Acyl-CoA Dehydrogenase Deficiency (VLCADD): Mutations in the ACADVL gene lead to impaired oxidation of very long-chain fatty acids, causing symptoms such as rhabdomyolysis, cardiomyopathy, and hepatomegaly.
4. Short-chain Acyl-CoA Dehydrogenase Deficiency (SCADD): Involves mutations in the ACADS gene, which may present with mild metabolic symptoms or remain asymptomatic.

Summary

Acyl-CoA dehydrogenases (ACADs) are essential enzymes in the β-oxidation pathway, responsible for the initial dehydrogenation of acyl-CoA substrates. This family of enzymes includes members specific for short-, medium-, long-, and very long-chain fatty acids, each playing crucial roles in fatty acid metabolism and energy production. ACAD deficiencies can lead to metabolic disorders characterized by impaired fatty acid oxidation and associated clinical symptoms, highlighting their importance in maintaining metabolic homeostasis.