The Acyl Coa Dehydrogenases

ACADs constitute a family of flavoproteins that catalyze the first step, an alpha, beta-dehydrogenation, in the beta-oxidation of fatty acids conjugated to CoA. The three-dimensional structures of six members of this family have been solved; they have a high degree of similarity and are characterized by a typical "MCAD-fold". The soluble members of the family are homotetramers composed of dimers of dimers. The cofactor FAD and the substrates are bound at the active center in extended conformations wherein the alpha,beta-position of the latter is positioned adjacent to the flavin N(5). A glutamate at the active center is positioned near the a-hydrogen of the substrate and serves in its abstraction as a proton, thereby initiating catalysis. During this process the beta-hydrogen is concomitantly transferred as a hydride to the N(5) of the flavin thereby reducing it. In the next step, electrons are transferred from the reduced flavin to the respiratory chain via electron transfer(ring) flavoprotein (ETF) and ETF-ubiquinone oxidoreductase. Some salient points that are relevant in the context of the (bio) chemical mechanisms of catalysis are discussed. Genetic defects are common in ACADs. Because ACADs play a central role in energy production and amino acid catabolism, their deficiencies are manifested in a variety of pediatric disorders. These deficiencies are discussed in some details for the most important cases.