ACADM - Acyl-CoA Dehydrogenase C-4 To C-12 Straight Chain |Elisa - Clia - Antibody - Protein

Background

Acyl-CoA dehydrogenase, C-4 to C-12 straight-chain, commonly abbreviated as ACADM, is a mitochondrial enzyme that plays a crucial role in fatty acid β-oxidation. This pathway is a primary mechanism for energy production, especially during fasting states when glucose reserves are low. ACADM specifically catalyzes the initial dehydrogenation step for medium-chain fatty acids (ranging from C4 to C12 in length) by oxidizing medium-chain acyl-CoA substrates to their corresponding trans-2-enoyl-CoA derivatives. The enzyme utilizes the cofactor flavin adenine dinucleotide (FAD) and transfers electrons to the electron transfer flavoprotein (ETF) in the mitochondrial respiratory chain.

Mutations in the ACADM gene, located on chromosome 1p31, lead to medium-chain acyl-CoA dehydrogenase deficiency (MCADD), one of the most common inborn errors of metabolism. This autosomal recessive disorder results in impaired fatty acid oxidation and severe metabolic complications, especially during fasting or periods of increased metabolic demand.

Protein Structure

The ACADM protein is a homotetramer, each subunit consisting of approximately 421 amino acids with a molecular weight of about 45 kDa. The enzyme is encoded by the ACADM gene and synthesized in the cytoplasm before being imported into mitochondria. Structural studies have revealed:

1. N-terminal Domain: This domain is responsible for FAD binding. The tight binding of FAD enables the redox activity required for the dehydrogenation of fatty acids. The FAD-binding motif is highly conserved across the acyl-CoA dehydrogenase family.
2. Active Site: The active site contains key residues, including glutamate and tyrosine, which participate in proton abstraction and electron transfer during catalysis. The active site is structured to accommodate medium-chain acyl-CoA substrates specifically.
3. C-terminal Domain: This domain contributes to substrate specificity and subunit interactions, stabilizing the tetrameric structure.
4. Electrostatic Surface: The enzyme’s surface has a distinct charge distribution that facilitates interaction with the ETF for efficient electron transfer.

Crystal structures have shown a compact fold typical of the acyl-CoA dehydrogenase family, with an α/β-barrel core and extended loops involved in substrate binding and specificity.

Classification and Subtypes

ACADM belongs to the acyl-CoA dehydrogenase family, which includes enzymes that act on fatty acids of varying chain lengths:

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

ACADM is specifically tailored to recognize and process medium-chain substrates, distinguishing it from other subtypes.

Function and Biological Significance

ACADM catalyzes the first step in the β-oxidation of medium-chain fatty acids by oxidizing acyl-CoA to trans-2-enoyl-CoA while reducing FAD to FADH2. This reaction is essential for:

• Energy Production: β-oxidation of fatty acids provides acetyl-CoA, which enters the citric acid cycle for ATP generation, particularly during fasting or prolonged exercise.
• Metabolic Adaptation: ACADM activity supports metabolic flexibility by enabling the body to utilize fat reserves efficiently.
• Homeostasis: Proper ACADM function maintains the balance of fatty acid and acyl-CoA derivatives, preventing the accumulation of toxic intermediates.

Clinical Issues

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

1. Pathophysiology: Mutations in the ACADM gene lead to reduced or absent enzyme activity. This results in the accumulation of medium-chain fatty acids and their derivatives, causing toxicity and energy deficits.
2. Symptoms: MCADD typically presents in infancy or early childhood, with symptoms including hypoglycemia, vomiting, lethargy, and, in severe cases, sudden death. Triggering factors include fasting, illness, or stress.
3. Diagnosis: Newborn screening with tandem mass spectrometry detects elevated medium-chain acylcarnitines in blood. Genetic testing confirms the diagnosis.
4. Treatment: Management involves preventing fasting, providing a high-carbohydrate diet during illness, and avoiding medium-chain triglycerides.

Other Clinical Implications:

• Impaired ACADM function has been linked to metabolic syndromes, including obesity and type 2 diabetes, although these associations are less well-established than MCADD.
• Emerging studies suggest that variations in fatty acid oxidation may influence the development of neurological and cardiac conditions.

Summary

ACADM is an essential enzyme in mitochondrial fatty acid oxidation, catalyzing the oxidation of medium-chain acyl-CoA substrates. Structurally, it is a flavoprotein with conserved domains for FAD binding and substrate interaction. The enzyme’s role in energy metabolism highlights its importance in maintaining metabolic homeostasis, especially during fasting states. Mutations in ACADM lead to MCADD, a condition that underscores the critical nature of this enzyme in human physiology. Continued research is vital to understanding the broader implications of ACADM dysfunction in metabolic health and disease.