HydroxyacylCoADehydrogenase

Hydroxyacyl-CoA refers to hydroxyacyl-CoA esters, especially 3-hydroxyacyl-CoA, which are intermediates in mitochondrial beta-oxidation of fatty acids. In this pathway, a fatty acyl-CoA is converted through successive steps that shorten the fatty acid by two carbon units per cycle. After the initial dehydrogenation and hydration steps, the resulting 3-hydroxyacyl-CoA is oxidized by 3-hydroxyacyl-CoA dehydrogenase to a 3-ketoacyl-CoA, which is then cleaved by thiolase to yield acetyl-CoA and a shortened acyl-CoA. This sequence repeats until the fatty acid is fully degraded for energy production.

Hydroxyacyl-CoA species arise for all chain lengths—short-, medium-, and long-chain forms are encountered in different tissues. In human mitochondria, the hydration step that produces the 3-hydroxyacyl-CoA is stereospecific, and the subsequent dehydrogenase step acts on the resulting intermediate to continue beta-oxidation. The enzymes involved include those associated with the mitochondrial trifunctional protein, which possesses activities required for the oxidation of long-chain hydroxyacyl-CoA substrates, as well as separate short- and medium-chain variants.

Clinical relevance includes metabolic disorders affecting beta-oxidation. Defects in long-chain 3-hydroxyacyl-CoA dehydrogenase activity, or in the mitochondrial trifunctional protein, cause LCHAD-related deficiencies. Patients may present with hypoketotic hypoglycemia, liver or cardiomyopathic symptoms, and neuropathy. Biochemical screening often detects elevated hydroxyacylcarnitines in plasma or urine, reflecting accumulation of hydroxyacyl-CoA derivatives that are converted to their carnitine esters.

See also: Beta-oxidation, Acyl-CoA, Acylcarnitine.