3-Ketoacyl-coenzyme A thiolase (KAT)

Molecular Classification

Enzyme, Thiolase superfamily, CoA-dependent enzyme

Other Names

3-ketoacyl-CoA thiolase, Thiolase I, Ketoacyl-CoA thiolase, 3-oxoacyl-CoA thiolase, KAT, MCKAT (medium-chain variant)

Disease Roles

Inborn errors of metabolism (e.g., beta-oxidation disorders)Energy metabolism disordersMetabolic decompensation (e.g., hypoglycemia, myopathy, hepatic dysfunction) in fatty acid oxidation deficiencies

3-Ketoacyl-coenzyme A thiolase Overview

3-Ketoacyl-coenzyme A thiolase (KAT) is an enzyme from the thiolase superfamily that catalyzes the thiolytic cleavage of 3-ketoacyl-CoA into acetyl-CoA and a shortened fatty acyl-CoA, representing the last step in the beta-oxidation of fatty acids in mitochondria and peroxisomes. KAT can also catalyze the reverse Claisen condensation reaction, enabling the carbon chain elongation of acyl-CoAs, which is exploited for synthetic biology and metabolic engineering, including bioproduction of value-added chemicals such as adipic acid and polyhydroxyalkanoates. There are isoforms in both mitochondria and peroxisomes, and deficiencies in these can result in inherited metabolic disorders characterized by disruption in fatty acid oxidation, leading to hypoketotic hypoglycemia and organ dysfunction. KAT is not a target of any approved therapeutic drugs but plays a crucial role in metabolic engineering and has been proposed as a drug discovery target for modulating fatty acid metabolism.

Mechanism of Action

Catalysis of thiolytic cleavage of 3-ketoacyl-CoA to acetyl-CoA and fatty acyl-CoA Claisen condensation of two acyl-CoA substrates for carbon chain elongation

Biological Functions

Fatty acid beta-oxidation

Degradation of long-, medium-, and short-chain fatty acids

Carbon chain elongation in metabolic pathways

Claisen condensation reaction

Disease Associations

Inborn errors of metabolism (e.g., beta-oxidation disorders)

Energy metabolism disorders

Metabolic decompensation (e.g., hypoglycemia, myopathy, hepatic dysfunction) in fatty acid oxidation deficiencies

Safety Considerations

Potential metabolic destabilization if inhibited in humans, leading to energy deficiency, hypoglycemia, and organ dysfunction
Low stability and substrate specificity hindering biotechnological applications

Interacting Drugs

None that are direct, clinically approved inhibitors or drugs in current therapeutics; KAT is a target in metabolic engineering and drug discovery contexts, but there are *no approved small-molecule drugs directly targeting this enzyme* in humans

Associated Biomarkers

Biomarker
Accumulated acylcarnitines in blood (biochemical marker for KAT deficiency)
Organic acids in urine (diagnostic for thiolase deficiency)
Fatty acid profiles (for inborn errors of beta-oxidation)