Carboxylesterase

Carboxylesterases are enzymes that hydrolyze carboxylic esters to alcohols and carboxylic acids. They are serine hydrolases belonging to the alpha/beta hydrolase fold and typically use a catalytic triad of serine, histidine, and an acidic residue. The reaction proceeds via formation of an acyl-enzyme intermediate, allowing diverse esters to be processed under mild physiological conditions.

These enzymes are widespread across life, from bacteria to humans. In humans, several CES genes encode major enzymes in the liver and intestine. The best characterized are CES1, highly expressed in the liver and a key player in hepatic drug metabolism, and CES2, abundant in the intestine and also active in the liver. Other family members include CES3, CES4, and CES5, with tissue expression that varies by gene and species. Structurally, carboxylesterases share features common to serine hydrolases and can be secreted or cytosolic, often functioning as glycoproteins.

In pharmacology and toxicology, carboxylesterases metabolize a broad range of xenobiotics and endogenous esters, and they commonly participate in prodrug activation as well as in drug inactivation. Substrates include capecitabine, activated to 5-fluorouracil by CES2; enalapril, activated to enalaprilat by hepatic esterases; and clopidogrel, which CES1 can hydrolyze to an inactive carboxylic acid metabolite. Activity can vary because of genetic polymorphisms, disease states, and drug interactions, influencing dosing and response.

Inhibitors such as organophosphates and carbamates can alter carboxylesterase activity, affecting drug clearance and toxicity. Beyond metabolism, these enzymes are exploited as biocatalysts in ester synthesis and bioremediation, reflecting their utility in pharmaceutical manufacturing and environmental applications.