carboxylesterases

Carboxylesterases are a family of serine hydrolases that catalyze the hydrolysis of carboxylic esters, converting esters into an alcohol and a carboxylic acid. They act on a broad range of substrates, including endogenous lipid esters and many xenobiotic esters, making them important for both normal physiology and detoxification of foreign compounds. In humans the best characterized enzymes are CES1 and CES2, encoded by the CES1 and CES2 genes, which show distinct tissue distribution and substrate preferences.

Structure and mechanism: Carboxylesterases belong to the alpha/beta hydrolase fold and use a catalytic triad of serine, histidine, and an acidic residue (glutamate or aspartate). The active serine resides in a conserved motif (a serine-containing GXSXG-like sequence) and acts as a nucleophile to attack the ester linkage, forming an acyl-enzyme intermediate that is then hydrolyzed to release products.

Expression and localization: CES1 is abundant in the liver and contributes to systemic drug metabolism, whereas CES2 is highly expressed in the small intestine and also participates in first-pass metabolism. Other family members, such as CES3 and CES5, have broader tissue distributions in various species.

Physiological and pharmacological relevance: Carboxylesterases metabolize endogenous esters and activate or deactivate many drugs and prodrugs. Examples include activation of oseltamivir by CES1 and conversion of irinotecan to the active metabolite SN-38 by CES2; CES1 also hydrolyzes certain antiplatelet prodrugs like clopidogrel to inactive forms. Genetic polymorphisms and drug interactions can significantly affect enzyme activity, influencing efficacy and risk of adverse effects.

Research and clinical implications: Variability in CES activity is a consideration in drug development and personalized therapy, as polymorphisms, disease states, or co-administered inhibitors can alter prodrug activation and detoxification of esters. Environmental organophosphates and some pesticides are known inhibitors of carboxylesterases.