Acyl-CoA dehydrogenase (ACAD)

Acyl-CoA dehydrogenases (ACADs) are a family of mitochondrial enzymes that catalyze the critical first step of the fatty acid beta-oxidation spiral. These enzymes work by introducing a double bond between the C2 (alpha) and C3 (beta) carbons of a fatty acyl-CoA thioester, utilizing Flavin Adenine Dinucleotide (FAD) as a mandatory cofactor (UniProt, PubMed). The family is categorized based on substrate chain-length specificity into short-chain (SCAD), medium-chain (MCAD), long-chain (LCAD), and very long-chain (VLCAD) acyl-CoA dehydrogenases, all of which are essential for mobilizing energy from fat stores during periods of fasting or increased energy demand (StatPearls). Clinical significance primarily arises from autosomal recessive deficiencies in these enzymes, with Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) being the most prevalent, leading to impaired ketogenesis and life-threatening hypoketotic hypoglycemia (NIH, PubMed). While primary management involves dietary avoidance of fasting, therapeutic interventions include riboflavin supplementation to stabilize mutant proteins and carnitine to assist in the clearance of toxic acyl intermediates. Recent studies also highlight the role of certain ACAD isoforms in supporting the metabolic flexibility of cancer cells, suggesting that targeted inhibition of these enzymes could serve as a strategy to disrupt tumor energy metabolism (Wikipedia, PubMed).

Other names

Fatty-acyl-CoA dehydrogenaseAcyl-CoA:acceptor 2,3-oxidoreductaseMitochondrial acyl-CoA dehydrogenaseFlavoenzyme acyl-CoA dehydrogenase

Cofactor supplementation (Riboflavin) to enhance residual enzyme activity and stability; Substrate replacement (Triheptanoin) to bypass blocked metabolic pathways; Irreversible inhibition by toxic metabolites (e.g., methylenecyclopropylacetyl-CoA from Hypoglycin A).