AcylCoADehydrogenase

Acyl-CoA dehydrogenases are a family of mitochondrial flavoprotein enzymes that catalyze the first and rate-limiting step of fatty acid beta-oxidation: the dehydrogenation of acyl-CoA to trans-2-enoyl-CoA. The reaction uses flavin adenine dinucleotide (FAD) as a prosthetic group, and the resulting electrons are transferred to the electron-transferring flavoprotein (ETF), which in turn passes them to the ubiquinone pool via ETF-ubiquinone oxidoreductase.

Isozymes in humans differ by substrate chain length. Very-long-chain acyl-CoA dehydrogenase (ACADVL) acts on long to very long chains; long-chain acyl-CoA dehydrogenase (ACADL) on long chains; medium-chain acyl-CoA dehydrogenase (ACADM) on medium chains; and short-chain acyl-CoA dehydrogenase (ACADS) on short chains. These enzymes are localized in the mitochondrial matrix and work in concert with other beta-oxidation enzymes and helper proteins to break down fatty acids for energy.

Deficiencies in acyl-CoA dehydrogenases cause fatty acid oxidation disorders. The most common is medium-chain acyl-CoA dehydrogenase deficiency (MCAD deficiency, ACADM). Others include very-long-chain acyl-CoA dehydrogenase deficiency (VLCAD deficiency, ACADVL) and, less commonly, short- or long-chain deficiencies (ACADS, ACADL). Clinical features can include hypoketotic hypoglycemia, hepatic dysfunction, cardiomyopathy, and rhabdomyolysis, often triggered by fasting or illness. Diagnosis typically involves newborn screening with acylcarnitine profiling and genetic testing. Management emphasizes avoidance of prolonged fasting, tailored dietary therapy (such as medium-chain triglycerides for certain disorders), and supportive care; carnitine supplementation may be used in some cases to aid excretion of accumulated metabolites.

Some acyl-CoA dehydrogenases, such as ACAD9, have additional roles in mitochondrial function beyond beta-oxidation, notably in assembly of respiratory chain complex I.