3-hydroxyacyl-CoA dehydrogenase

3-Hydroxyacyl-CoA dehydrogenase (HADH) is an enzyme that plays a crucial role in the metabolism of fatty acids within the body. It is involved in the mitochondrial fatty acid beta-oxidation pathway, a critical process for the production of energy from fats. This enzyme catalyzes the third step in the beta-oxidation cycle, specifically the oxidation of 3-hydroxyacyl-CoA to 3-ketoacyl-CoA, while simultaneously reducing nicotinamide adenine dinucleotide (NAD+) to NADH.

Function

The primary function of 3-hydroxyacyl-CoA dehydrogenase is to facilitate the conversion of 3-hydroxyacyl-CoA, a product of fatty acid oxidation, into its keto form. This reaction is essential for the continuous breakdown of fatty acids, allowing for the release of acetyl-CoA, which enters the citric acid cycle (also known as the Krebs cycle), ultimately leading to the production of ATP, the energy currency of the cell.

Structure

3-Hydroxyacyl-CoA dehydrogenase is a protein that is encoded by the HADH gene in humans. The enzyme is located in the mitochondrial matrix, reflecting its role in the mitochondrial fatty acid beta-oxidation pathway. The structure of HADH has been elucidated through various biochemical and biophysical methods, revealing a homotetrameric organization in some species, with each subunit containing a catalytic domain and a NAD+ binding site.

Clinical Significance

Mutations in the HADH gene can lead to a rare metabolic disorder known as 3-Hydroxyacyl-CoA Dehydrogenase Deficiency or HADH deficiency. This condition is characterized by an inability to properly metabolize certain types of fatty acids, leading to a buildup of toxic intermediates in the body. Symptoms can include hypoglycemia, lethargy, hypotonia, and in severe cases, metabolic acidosis. Diagnosis often involves biochemical assays to detect abnormalities in fatty acid metabolism, and genetic testing to identify mutations in the HADH gene.

Treatment and Management

Management of HADH deficiency typically involves dietary modifications to limit the intake of long-chain fatty acids and fasting avoidance to reduce the risk of hypoglycemia. In some cases, medium-chain triglycerides (MCT) oil supplements may be recommended, as MCTs are metabolized differently and do not require HADH for their oxidation.

Research Directions

Ongoing research is focused on better understanding the molecular mechanisms underlying HADH function and its role in fatty acid metabolism. Studies are also aimed at developing more effective treatments for HADH deficiency and related metabolic disorders, including gene therapy and novel pharmacological approaches.

See Also

• Fatty acid metabolism
• Mitochondrial diseases
• Metabolic disorders