Acyl-CoA dehydrogenase
Acyl-CoA dehydrogenases (ACADs) are a class of enzymes that function to catalyze the initial step in each cycle of fatty acid β-oxidation in the mitochondria of cells.
[1] Flavin adenine dinucleotide (FAD) is a required co-factor in addition to the presence of an active site glutamate in order for the enzyme to function.
[2] ACADs are an important class of enzymes in mammalian cells because of their role in metabolizing fatty acids present in ingested food materials.
An additional class of acyl-CoA dehydrogenase was discovered that catalyzes α,β-unsaturation reactions with steroid-CoA thioesters in certain types of bacteria.
[8][9] This class of ACAD was demonstrated to form α2β2 heterotetramers, rather than the usual α4 homotetramer, a protein architecture that evolved in order to accommodate a much larger steroid-CoA substrate.
The medium chain acyl-CoA dehydrogenase (MCAD) is the best known structure of all ACADs, and is the most commonly deficient enzyme within the class that leads to metabolic disorders in animals.
[12] A novel ACAD enzyme architecture in some species of steroid-utilizing bacteria (Actinomycetota and Pseudomonadota) was discovered, and is involved in the utilization of ubiquitous steroid substrates like cholesterol by pathogenic organisms like Mycobacterium tuberculosis.
[1] Deficiencies in acyl-CoA dehydrogenases result in decreased ability to oxidize fatty acids, thereby signifying metabolic dysfunction.
Some symptoms of medium-chain acyl-CoA dehydrogenase deficiency include intolerance to fasting, hypoglycemia, and sudden infant death syndrome.
Approximately 90% of cases of MCAD are due to a single point mutation where the lysine at position 304 (Lys304) is replaced by a glutamate residue and this prevents the enzyme from properly functioning.
When a mutation causes glutamate to take the place of lysine, an additional negative charge is introduced at that site, which disrupts the normally occurring H-bonding.
Such a disruption alters the folding pattern of the enzyme, ultimately compromising its stability and inhibiting its function in fatty acid oxidation.
