ACADSB - Acyl-CoA Dehydrogenase, Short/Branched Chain |Elisa - Clia - Antibody - Protein

Background

Acyl-CoA dehydrogenase, short/branched chain (ACADSB), is a mitochondrial enzyme responsible for the initial step of β-oxidation in short-chain and branched-chain fatty acids. It primarily catalyzes the dehydrogenation of isobutyryl-CoA, derived from the catabolism of valine, as well as other branched-chain and straight-chain acyl-CoAs of short-chain length. The enzyme is crucial for energy production from these substrates and helps maintain amino acid and fatty acid metabolic balance.

The ACADSB gene is located on chromosome 10q25.1 and encodes the ACADSB protein. Mutations in this gene lead to isobutyryl-CoA dehydrogenase deficiency, an autosomal recessive disorder characterized by impaired valine metabolism. While often asymptomatic, severe cases can result in metabolic disturbances, myopathy, and developmental delays.

Protein Structure

The ACADSB enzyme is a homotetramer, similar to other members of the acyl-CoA dehydrogenase family. Each monomer has approximately 400-420 amino acids, with a molecular weight of about 44 kDa. Its structural components include:

Flavin Adenine Dinucleotide (FAD) Binding Site:

• ACADSB contains a conserved FAD-binding domain near its N-terminus. FAD acts as a cofactor, accepting electrons from the substrate and transferring them to electron transfer flavoproteins (ETFs) during fatty acid oxidation.

Active Site:

• The enzyme's active site includes residues critical for substrate binding and catalysis. A glutamate residue typically facilitates proton abstraction, while adjacent residues stabilize the substrate during the reaction.

Tetrameric Quaternary Structure:

• The functional enzyme exists as a tetramer, with subunit interfaces stabilized by hydrogen bonds and hydrophobic interactions. This structure is essential for enzymatic activity.

Substrate-Binding Pocket:

• The pocket is designed to accommodate both short-chain and branched-chain acyl-CoA derivatives. Specific interactions between the enzyme and substrates confer its unique activity toward isobutyryl-CoA.

The enzyme resides in the mitochondrial matrix, where it interacts with ETF to shuttle electrons into the respiratory chain, linking fatty acid and amino acid catabolism with ATP production.

Classification and Subtypes

ACADSB belongs to the acyl-CoA dehydrogenase family, which is classified based on substrate specificity:

• Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD): Acts on fatty acids >20 carbons.
• Long-Chain Acyl-CoA Dehydrogenase (LCAD): Acts on fatty acids of 12-20 carbons.
• Medium-Chain Acyl-CoA Dehydrogenase (MCAD): Targets fatty acids of 6-12 carbons.
• Short-Chain Acyl-CoA Dehydrogenase (SCAD): Works on fatty acids with 4-6 carbons.
• Short/Branched-Chain Acyl-CoA Dehydrogenase (ACADSB): Specializes in isobutyryl-CoA and other branched-chain acyl-CoA derivatives.

ACADSB is unique in its ability to dehydrogenate branched-chain fatty acids, particularly those arising from valine catabolism.

Function and Biological Significance

ACADSB is critical for both energy production and intermediary metabolism:

Fatty Acid Oxidation:

• Catalyzes the first step in β-oxidation of short-chain and branched-chain fatty acids. This process generates energy-rich acetyl-CoA, which enters the citric acid cycle for ATP production.

Amino Acid Metabolism:

• Plays a key role in the degradation of valine, a branched-chain amino acid. Valine is converted into isobutyryl-CoA, which is further processed through the β-oxidation pathway facilitated by ACADSB.

Energy Homeostasis:

• During fasting or metabolic stress, ACADSB contributes to maintaining glucose levels by oxidizing fatty acids and producing ketone bodies as alternative energy sources.

Detoxification:

• Prevents the accumulation of branched-chain acyl-CoA intermediates, which can be toxic in excess.

Clinical Issues

Isobutyryl-CoA Dehydrogenase Deficiency:

Pathophysiology:

• Mutations in the ACADSB gene impair enzyme activity, leading to the accumulation of isobutyryl-CoA and its derivatives. This disruption primarily affects valine metabolism and can result in secondary metabolic derangements.

Symptoms:

• Many individuals are asymptomatic, but severe cases may present with:
• Developmental delays
• Lethargy
• Hypotonia
• Myopathy
• Elevated levels of isobutyrylcarnitine (C4-acylcarnitine) in blood

Diagnosis:

• Newborn Screening: Elevated C4-acylcarnitine levels detected by tandem mass spectrometry.
• Genetic Testing: Identification of pathogenic variants in the ACADSB gene.
• Biochemical Testing: Urine organic acid analysis to detect excess isobutyryl-CoA derivatives.

Treatment:

• Management primarily involves dietary restrictions to limit valine intake.
• Carnitine supplementation may be used to enhance excretion of acylcarnitines.

Prognosis:

• The prognosis is generally favorable with early diagnosis and intervention. Most cases are mild and manageable with appropriate metabolic care.

Summary

ACADSB is a mitochondrial enzyme specializing in the β-oxidation of short-chain and branched-chain fatty acids, particularly isobutyryl-CoA from valine metabolism. Its homotetrameric structure, featuring an FAD-binding site and substrate-specific active site, enables its function in energy production and metabolic regulation. Deficiency of ACADSB due to genetic mutations causes isobutyryl-CoA dehydrogenase deficiency, a rare metabolic disorder with variable clinical severity. Advances in understanding ACADSB's role in metabolism and disease continue to inform strategies for diagnosis and treatment, emphasizing its importance in human health.