Ketothiolase

Ketothiolase, also known as acetoacetyl-CoA thiolase or beta-ketothiolase, is a mitochondrial enzyme that participates in ketone body metabolism and fatty acid beta-oxidation. It catalyzes the thiolytic cleavage of acetoacetyl-CoA to produce two molecules of acetyl-CoA, a key step in converting ketone bodies into energy and in the final stages of fatty acid oxidation.

In humans, the enzyme is encoded by the ACAA2 gene and located in the mitochondria of many tissues, including liver, heart, and muscle. The primary reaction is acetoacetyl-CoA + CoA-SH → 2 acetyl-CoA. The reaction is effectively reversible, linking ketone body utilization to the acetyl-CoA pool. A related thiolase catalyzes the preceding condensation of two acetyl-CoA to form acetoacetyl-CoA, which feeds into ketone body synthesis in the liver.

Ketothiolase participates in metabolic pathways that generate and utilize acetyl-CoA during fasting, prolonged exercise, and certain metabolic states. It also plays a role in the breakdown of specific amino-acid–derived carbon skeletons that enter the acetoacetyl-CoA pool. The enzyme belongs to the thiolase family and shares a catalytic mechanism that uses a reactive cysteine residue to form a covalent acyl-enzyme intermediate, with histidine and other residues acting as acid–base partners during the thiolase reaction.

Clinical significance: beta-ketothiolase deficiency is a rare inborn error of metabolism caused by impaired acetoacetyl-CoA thiolase activity. It can present with episodic ketoacidosis, hypoglycemia, and metabolic acidosis, often during fasting or illness. Diagnosis relies on biochemical testing for characteristic organic acid and acetoacetate profiles; management focuses on preventing fasting and providing careful dietary support.