Mitochondrial long-chain 3-ketoacyl coenzyme A thiolase (HADHB) (HADHB)

Mitochondrial long-chain 3-ketoacyl coenzyme A thiolase (HADHB) is a critical enzyme located within the mitochondrial matrix that catalyzes the final step of the fatty acid beta-oxidation spiral for long-chain fatty acids (UniProt P55084). It functions as the beta subunit of the mitochondrial trifunctional protein (MTP), a hetero-octameric complex that also possesses hydratase and dehydrogenase activities (PubMed PMID: 15159443). By converting 3-ketoacyl-CoA into acetyl-CoA and a shortened acyl-CoA chain, this enzyme plays a vital role in cellular energy production, particularly in high-demand tissues like the heart and skeletal muscle (StatPearls: Fatty Acid Oxidation). In clinical medicine, HADHB is a therapeutic target for anti-ischemic drugs such as trimetazidine, which inhibit its activity to favor glucose oxidation over fatty acid oxidation, improving myocardial oxygen efficiency (PubChem CID 5574). This metabolic shift is particularly beneficial in treating stable angina pectoris and heart failure by reducing the oxygen demand of the myocardium (PubMed PMID: 11014404). Genetic mutations in the HADHB gene lead to mitochondrial trifunctional protein deficiency, a severe metabolic disorder characterized by cardiomyopathy, skeletal myopathy, and hypoglycemia (NIH: MedlinePlus Genetics). Therapeutic challenges include managing the risk of Parkinsonian symptoms associated with pharmacological inhibition and the complex metabolic management required for patients with genetic deficiencies (EMA: Trimetazidine safety review).

Other names

3-ketoacyl-CoA thiolaseBeta-ketothiolaseHydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit betaTP-betaECHBLong-chain 3-ketoacyl-CoA thiolaseMitochondrial trifunctional protein subunit beta

Inhibition of the enzyme shifts myocardial energy metabolism from fatty acid oxidation to glucose oxidation, which requires less oxygen per unit of ATP produced, thereby protecting the heart during ischemia (PubMed PMID: 11014404).