3-hydroxyacyl-CoA dehydrogenase
Introduction
3-hydroxyacyl-CoA dehydrogenase (HADH) is an enzyme that plays a crucial role in the beta oxidation pathway, a metabolic process that breaks down fatty acids to produce energy. It is a member of the short-chain dehydrogenase/reductase (SDR) superfamily, which is characterized by the presence of a conserved catalytic triad of residues. The enzyme is encoded by the HADH gene in humans.
Structure
HADH is a tetrameric enzyme, with each subunit containing a Rossmann fold domain for NAD+ binding and a substrate-binding domain. The active site of the enzyme is located in a deep pocket at the interface of these two domains. The catalytic triad, consisting of Serine, Tyrosine, and Lysine residues, is found within this active site.
Function
HADH catalyzes the third step in the beta oxidation pathway, the conversion of L-3-hydroxyacyl-CoA to 3-ketoacyl-CoA. This reaction involves the oxidation of a hydroxyl group to a keto group, with the concomitant reduction of NAD+ to NADH. The NADH produced is then used in the electron transport chain to generate ATP, the main energy currency of the cell.
Clinical Significance
Mutations in the HADH gene can lead to 3-hydroxyacyl-CoA dehydrogenase deficiency, a rare autosomal recessive disorder characterized by hypoglycemia, hyperinsulinism, and developmental delay. This condition is typically diagnosed in infancy and can be managed with a diet low in long-chain fatty acids and high in carbohydrates.
Research
Research into HADH has focused on understanding its structure and function, as well as its role in disease. Studies have used techniques such as X-ray crystallography to determine the enzyme's structure, and biochemical assays to study its catalytic activity. In addition, genetic studies have identified mutations in the HADH gene that cause 3-hydroxyacyl-CoA dehydrogenase deficiency, providing insight into the molecular basis of this disorder.