acylCoAd

Acyl-CoA dehydrogenases (ACADs) are a family of flavoprotein enzymes that catalyze the first oxidative step in the mitochondrial beta-oxidation of fatty acids. They convert acyl-CoA substrates into the corresponding trans-2-enoyl-CoA while reducing flavin adenine dinucleotide (FAD) to FADH2, with electrons subsequently transferred to the electron-transfer flavoprotein (ETF) and into the respiratory chain. These enzymes are encoded by nuclear genes and are targeted to mitochondria, where they function in fatty acid catabolism across different tissue types.

Substrate specificity within the ACAD family varies by isoform and chain length. Short-chain acyl-CoA dehydrogenase (ACADS) acts on short-chain acyl-CoAs (roughly C4–C6), medium-chain acyl-CoA dehydrogenase (ACADM) on medium-chain substrates (about C6–C12), long-chain acyl-CoA dehydrogenase (ACADL) on longer chains (roughly C12–C14), and very-long-chain acyl-CoA dehydrogenase (ACADVL) on very-long-chain substrates (C14–C20). Other members, such as ACAD9, participate in long-chain beta-oxidation and may have additional roles in mitochondrial complex I assembly.

Defects in ACAD enzymes cause fatty acid oxidation disorders (FAODs). The most common is MCAD deficiency (ACADM), presenting with hypoketotic hypoglycemia during fasting or illness. Other FAODs include VLCAD deficiency (ACADVL) and SCAD deficiency (ACADS). Diagnosis combines newborn screening and acylcarnitine profiling, with management emphasizing avoidance of prolonged fasting and prompt treatment of metabolic crises. ACAD-related disorders illustrate the crucial role of acyl-CoA dehydrogenases in cellular energy production from fatty acids.