ACADVL - Very Long-Chain Specific Acyl-CoA Dehydrogenase MitochondriaL |Elisa - Clia - Antibody - Protein

Background

Very Long-Chain Acyl-CoA Dehydrogenase (ACADVL) is a mitochondrial enzyme critical for the β-oxidation of long-chain fatty acids, specifically those with carbon chain lengths of 14 to 20. This process is essential for energy production, particularly during fasting or periods of increased energy demand, such as exercise or illness. ACADVL catalyzes the first dehydrogenation step in the breakdown of very long-chain fatty acids, resulting in the formation of a trans-double bond between the β- and α-carbons of the acyl-CoA substrate.

Encoded by the ACADVL gene located on chromosome 17p13.1, mutations in this gene are associated with Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD), an autosomal recessive metabolic disorder. VLCADD manifests with varying clinical severity, ranging from mild muscle weakness to life-threatening cardiomyopathy and hypoketotic hypoglycemia.

Protein Structure

ACADVL is a homotetrameric flavoprotein that is structurally and functionally distinct among the acyl-CoA dehydrogenase family. Key structural features include:

Amino Acid Sequence and Domains:

• The mature protein comprises ~655 amino acids with a molecular weight of approximately 70 kDa per monomer.
• It contains conserved regions characteristic of acyl-CoA dehydrogenases, including an N-terminal mitochondrial targeting sequence that directs the precursor protein to the mitochondria.

Flavin Adenine Dinucleotide (FAD) Binding:

• ACADVL uses FAD as a prosthetic group, which facilitates the transfer of electrons from very long-chain acyl-CoA substrates to electron transfer flavoproteins (ETFs) in the mitochondrial matrix.

Active Site:

• The active site contains residues essential for catalysis, including a catalytic glutamate that abstracts a proton from the substrate's β-carbon.
• The hydrophobic substrate-binding pocket accommodates very long-chain acyl-CoAs, imparting specificity to ACADVL.

Quaternary Structure:

• ACADVL functions as a homotetramer, with subunit interfaces stabilized by hydrogen bonds and hydrophobic interactions. The tetrameric structure is necessary for enzymatic stability and activity.

Substrate Specificity:

• Structural studies reveal that ACADVL has a larger and more hydrophobic substrate-binding pocket compared to other acyl-CoA dehydrogenases, allowing it to process very long-chain fatty acids.

Localization:

• ACADVL is localized in the mitochondrial matrix, where it interacts with ETFs to transfer electrons to the respiratory chain, linking fatty acid β-oxidation with ATP production.

Classification and Subtypes

ACADVL belongs to the acyl-CoA dehydrogenase family, which is classified based on substrate chain length:

• Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD): 14–20 carbon chains.
• Long-Chain Acyl-CoA Dehydrogenase (LCAD): 12–20 carbon chains.
• Medium-Chain Acyl-CoA Dehydrogenase (MCAD): 6–12 carbon chains.
• Short-Chain Acyl-CoA Dehydrogenase (SCAD): 4–6 carbon chains.
• Branched-Chain Acyl-CoA Dehydrogenases: Specific for branched substrates.

VLCAD is unique in its activity on long-chain fatty acids, which makes it indispensable for mitochondrial fatty acid oxidation.

Function and Biological Significance

ACADVL plays a crucial role in cellular energy metabolism:

Catalysis of β-Oxidation:

• Catalyzes the first and rate-limiting step of β-oxidation for very long-chain fatty acids. The reaction converts very long-chain acyl-CoAs into trans-2-enoyl-CoAs, with the concurrent reduction of FAD to FADH₂.

Energy Production:

• Fatty acid oxidation in mitochondria generates acetyl-CoA, NADH, and FADH₂, which feed into the citric acid cycle and electron transport chain for ATP production.

Ketogenesis:

• During fasting or carbohydrate deprivation, ACADVL-mediated fatty acid oxidation contributes to ketone body production, providing an alternative energy source for peripheral tissues, including the brain.

Protection Against Lipid Accumulation:

• Prevents the accumulation of toxic very long-chain fatty acids and their derivatives, which can disrupt cellular function and cause organ damage.

Metabolic Flexibility:

• VLCAD enables metabolic flexibility, allowing cells to switch between carbohydrate and lipid oxidation depending on energy demands.

Clinical Issues

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

Pathophysiology:

• VLCADD results from mutations in the ACADVL gene, leading to reduced or absent VLCAD activity. This disrupts mitochondrial fatty acid oxidation, resulting in the accumulation of very long-chain fatty acids and their intermediates.

Clinical Presentation:

VLCADD exhibits variable clinical phenotypes:

• Severe Neonatal-Onset Form: Hypoketotic hypoglycemia, hepatomegaly, and cardiomyopathy, often life-threatening.
• Childhood-Onset Form: Intermittent hypoglycemia, myopathy, and lethargy, triggered by fasting or illness.
• Adult-Onset Form: Exercise-induced muscle weakness, rhabdomyolysis, and myoglobinuria.

Diagnosis:

• Newborn Screening: Elevated levels of C14-C18 acylcarnitines detected by tandem mass spectrometry.
• Genetic Testing: Identification of pathogenic ACADVL variants.
• Enzyme Activity Assays: Measurement of VLCAD activity in fibroblasts or lymphocytes.

Treatment:

• Dietary Management: Avoidance of fasting and long-chain triglycerides, supplemented with medium-chain triglycerides (MCTs) for energy.
• Supplementation: Carnitine and riboflavin supplementation to enhance fatty acid oxidation and electron transfer.
• Emergency Management: Intravenous glucose and lipid infusion during metabolic crises.

Prognosis:

• Early diagnosis and management improve outcomes, but severe neonatal cases carry a higher risk of morbidity and mortality.

Summary

ACADVL is a mitochondrial enzyme essential for the β-oxidation of very long-chain fatty acids. Its homotetrameric structure and FAD-binding active site enable it to dehydrogenate acyl-CoAs with carbon chain lengths of 14 to 20. Mutations in the ACADVL gene cause VLCADD, a disorder with diverse clinical phenotypes, from life-threatening neonatal symptoms to mild adult-onset muscle weakness. Understanding ACADVL's role in energy metabolism and its associated disorders has facilitated advancements in diagnostic and therapeutic approaches, emphasizing its importance in human physiology and metabolic health..