Hydroxyacyl-CoA dehydrogenase (HADH)

Hydroxyacyl-CoA dehydrogenase (HADH) is a vital mitochondrial enzyme that catalyzes the third step of the fatty acid beta-oxidation pathway, specifically the NAD+-dependent oxidation of 3-hydroxyacyl-CoA to 3-ketoacyl-CoA [7, 13]. This enzymatic activity is essential for the breakdown of fatty acids into acetyl-CoA, which then enters the citric acid cycle for energy production [2, 8]. In humans, this function is carried out by several distinct proteins, including the short-chain specific HADH (Type 1) and the long-chain specific alpha subunit of the mitochondrial trifunctional protein (HADHA) [6, 9]. HADH plays a significant role in systemic glucose homeostasis; its deficiency is a known cause of congenital hyperinsulinemic hypoglycemia due to the loss of its inhibitory effect on glutamate dehydrogenase, leading to excessive insulin secretion [3, 7]. In the context of oncology, HADH and its isoforms (particularly HADHA) are frequently overexpressed in various malignancies, such as malignant lymphoma and glioblastoma, where they facilitate metabolic reprogramming to support rapid tumor growth and survival [1, 5, 10]. Therapeutic targeting of these enzymes, such as with the drug trimetazidine, aims to shift cellular metabolism from fatty acid oxidation to glucose oxidation, offering potential benefits in treating ischemic heart disease and certain cancers [2, 9].

Other names

Short-chain L-3-hydroxyacyl-CoA dehydrogenaseSCHADHCDHHAD3-hydroxyacyl-CoA dehydrogenaseMitochondrial trifunctional protein alpha subunit (HADHA)Mitochondrial trifunctional protein beta subunit (HADHB)L-3-hydroxyacyl-CoA dehydrogenase

Inhibition of mitochondrial fatty acid beta-oxidation and modulation of cellular metabolic pathways