Hydroxyacyl-CoA dehydrogenase trifunctional protein subunit alpha (HADHA) (HADHA)

Hydroxyacyl-CoA dehydrogenase trifunctional protein subunit alpha (HADHA) is a multi-functional enzyme located within the mitochondrial matrix, serving as a key component of the mitochondrial trifunctional protein (MTP) complex (UniProt: P30084). It is responsible for two of the four steps in the beta-oxidation of long-chain fatty acids: the hydration of enoyl-CoA to 3-hydroxyacyl-CoA and the subsequent dehydrogenation to 3-ketoacyl-CoA (NCBI Gene: 3030). This process is essential for generating cellular energy from stored fats, particularly during periods of fasting or prolonged exercise (StatPearls: Fatty Acid Oxidation Disorders). Mutations in the HADHA gene are the primary cause of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and can contribute to complete MTP deficiency, both of which are life-threatening metabolic disorders (OMIM: 600890). Furthermore, fetal HADHA mutations are strongly associated with maternal complications such as Acute Fatty Liver of Pregnancy (AFLP) and HELLP syndrome (PubMed: 15528790). While there are currently no FDA-approved drugs that specifically target HADHA for therapeutic inhibition, it is known to be inhibited by certain compounds like salicylates and is a subject of study in cancer metabolism and metabolic disease research (PubMed: 11013305). Understanding the structural and functional properties of HADHA is critical for the development of targeted therapies for fatty acid oxidation disorders and for identifying potential drug-induced metabolic toxicities (PubMed: 1705130).

Other names

Mitochondrial trifunctional protein subunit alphaLong-chain enoyl-CoA hydrataseLong-chain 3-hydroxyacyl-CoA dehydrogenaseLCHAD78 kDa gastrin-binding proteinTP-alphaHADHA

Inhibition of the long-chain 3-hydroxyacyl-CoA dehydrogenase activity, leading to the disruption of mitochondrial fatty acid beta-oxidation (PubMed: 11013305).