ACADS - Acyl-CoA Dehydrogenase, Short Chain |Elisa - Clia - Antibody - Protein

Background

Acyl-CoA dehydrogenase, short-chain (ACADS), is a mitochondrial enzyme crucial for the β-oxidation of short-chain fatty acids (SCFAs). This enzyme catalyzes the dehydrogenation of acyl-CoA derivatives, specifically those containing 4 to 6 carbon atoms, converting them into trans-2-enoyl-CoA intermediates. This reaction is a key initial step in the energy production pathway, particularly under fasting conditions when fatty acid oxidation becomes a primary energy source.

The ACADS gene, located on chromosome 12q22-q24.1, encodes the ACADS protein. Mutations in this gene cause short-chain acyl-CoA dehydrogenase deficiency (SCADD), a rare autosomal recessive metabolic disorder characterized by impaired fatty acid oxidation, leading to energy deficits and potential metabolic crises. SCADD may manifest with a spectrum of symptoms ranging from mild to severe, often triggered by fasting or illness.

Protein Structure

The ACADS protein is a homotetramer, with each monomer comprising approximately 412 amino acids and having a molecular weight of around 44 kDa. Key structural features include:

1. N-terminal Domain: This domain contains a highly conserved FAD-binding site, critical for the enzyme's catalytic activity. Flavin adenine dinucleotide (FAD) acts as a cofactor, facilitating the electron transfer process during fatty acid oxidation.
2. Active Site: The active site includes residues essential for catalysis, such as glutamate, which functions in proton abstraction, and tyrosine, which stabilizes the substrate. The substrate-binding pocket is tailored to short-chain acyl-CoA molecules, allowing for high specificity.
3. C-terminal Domain: The C-terminal contributes to substrate recognition and helps maintain the enzyme's overall structural stability. It also plays a role in tetramerization, essential for functional activity.
4. Tetrameric Structure: The ACADS enzyme functions as a tetramer, with subunits interacting through non-covalent bonds. This quaternary structure is crucial for the stability and activity of the enzyme, ensuring efficient fatty acid processing.

The enzyme is localized to the mitochondrial matrix, where it interacts with electron transfer flavoproteins (ETF) to transfer electrons into the respiratory chain, linking fatty acid oxidation to ATP synthesis.

Classification and Subtypes

ACADS is a member of the acyl-CoA dehydrogenase enzyme family, categorized based on the chain-length specificity of their fatty acid substrates:

• Short-chain acyl-CoA dehydrogenase (SCAD): Acts on fatty acids with 4-6 carbons.
• Medium-chain acyl-CoA dehydrogenase (MCAD): Processes fatty acids with 6-12 carbons.
• Long-chain acyl-CoA dehydrogenase (LCAD): Acts on fatty acids with 12-18 carbons.
• Very-long-chain acyl-CoA dehydrogenase (VLCAD): Targets fatty acids longer than 18 carbons.

ACADS specifically targets short-chain fatty acids, distinguishing it from other family members by its substrate specificity and kinetic properties.

Function and Biological Significance

ACADS plays a pivotal role in mitochondrial fatty acid β-oxidation by catalyzing the dehydrogenation of short-chain acyl-CoA substrates to trans-2-enoyl-CoA. This step is critical for:

1. Energy Metabolism: SCFAs generated from dietary fats or lipid stores are oxidized to acetyl-CoA, which enters the citric acid cycle and generates ATP through oxidative phosphorylation.
2. Ketogenesis: During fasting or low glucose availability, ACADS contributes to the production of ketone bodies, an alternative energy source for peripheral tissues, including the brain.
3. Metabolic Regulation: By processing short-chain fatty acids, ACADS helps maintain metabolic homeostasis and prevents the accumulation of potentially toxic acyl-CoA derivatives.

Clinical Issues

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

Pathophysiology: Mutations in the ACADS gene impair the enzyme's activity, leading to reduced β-oxidation of short-chain fatty acids. This results in the accumulation of metabolites such as butyrylcarnitine and ethylmalonic acid, which can have toxic effects.

Symptoms: SCADD is highly variable in clinical presentation. While many individuals remain asymptomatic, others may experience:

• Hypoglycemia
• Muscle weakness or hypotonia
• Developmental delays
• Vomiting and lethargy during metabolic stress

Diagnosis: Diagnostic approaches include:

• Newborn screening: Elevated levels of butyrylcarnitine (C4-acylcarnitine) in dried blood spots.
• Genetic testing: Identification of pathogenic variants in the ACADS gene.
• Biochemical assays: Measurement of ethylmalonic acid in urine and butyrylcarnitine in plasma.

Treatment: Management strategies focus on preventing metabolic crises through:

• Frequent feeding to avoid fasting
• High-carbohydrate, low-fat diets
• Supplementation with carnitine to facilitate the excretion of accumulated fatty acid metabolites

Other Clinical Associations: Emerging research suggests that variations in ACADS activity may influence broader metabolic conditions, including insulin resistance and lipid metabolism disorders. However, these associations require further investigation.

Summary

ACADS is a mitochondrial enzyme essential for the β-oxidation of short-chain fatty acids, linking fatty acid metabolism to cellular energy production. Structurally, it is a homotetramer with specialized domains for FAD binding and substrate recognition. The enzyme's role in maintaining energy homeostasis underscores its importance in human metabolism. Mutations in the ACADS gene result in SCADD, a disorder with variable clinical severity, emphasizing the need for early diagnosis and metabolic management. The continued study of ACADS and its interactions within the metabolic network holds promise for advancing our understanding of metabolic health and disease.