Thioesterase

Thioesterase is a general term for enzymes that catalyze the hydrolysis of thioester bonds, breaking them to yield a free carboxylate and a thiol. The canonical reaction can be summarized as R-CO-S-R' + H2O → R-COO− + HS-R'. Thioesterases act on thioester-containing substrates found in metabolism and biosynthesis.

In biology, thioesterases play key roles in lipid metabolism and detoxification. Acyl-CoA thioesterases (ACOTs) hydrolyze acyl-CoA thioesters to free fatty acids and CoA, thereby modulating the balance between acyl-CoA and CoA pools, influencing energy homeostasis and signaling pathways. ACOTs are found in various tissues and subcellular compartments, including the cytosol, mitochondria, and peroxisomes, reflecting diverse functional needs.

Thioesterases are also essential in biosynthetic pathways such as fatty acid synthesis and polyketide/peptide assembly. In fatty acid synthase and polyketide synthase systems, terminal thioesterase domains release the growing product from the assembly line. Release can result in a free fatty acid or, in many polyketide pathways, a macrolactone via intramolecular cyclization, depending on the enzyme specificities and substrates involved.

Structural and mechanistic diversity characterizes thioesterases. They include families such as hot dog fold enzymes and alpha/beta hydrolase fold enzymes. Many operate through serine- or metal-assisted hydrolase mechanisms and show a range of substrate specificities, from short-chain to long-chain fatty acyl thioesters.

Applications and relevance include roles in metabolic regulation and opportunities for pathway engineering in biotechnology. Understanding thioesterases informs both metabolic disease research and the rational design of biosynthetic routes for tailored lipid-derived products.