Structure and Catalytic Properties of Carboxylesterase Isozymes Involved in Metabolic Activation of Prodrugs
AbstractMammalian carboxylesterases (CESs) comprise a multigene family whose geneproducts play important roles in biotransformation of ester- or amide-type prodrugs. Theyare members of an α,β-hydrolase-fold family and are found in various mammals. It has beensuggested that CESs can be classified into five major groups denominated CES1-CES5,according to the homology of the amino acid sequence, and the majority of CESs that havebeen identified belong to the CES1 or CES2 family. The substrate specificities of CES1 andCES2 are significantly different. The CES1 isozyme mainly hydrolyzes a substrate with asmall alcohol group and large acyl group, but its wide active pocket sometimes allows it toact on structurally distinct compounds of either a large or small alcohol moiety. In contrast,the CES2 isozyme recognizes a substrate with a large alcohol group and small acyl group,and its substrate specificity may be restricted by the capability of acyl-enzyme conjugateformation due to the presence of conformational interference in the active pocket. Sincepharmacokinetic and pharmacological data for prodrugs obtained from preclinicalexperiments using various animals are generally used as references for human studies, it isimportant to clarify the biochemical properties of CES isozymes. Further experimentationfor an understanding of detailed substrate specificity of prodrugs for CES isozymes and itshydrolysates will help us to design the ideal prodrugs.
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Hosokawa, M. Structure and Catalytic Properties of Carboxylesterase Isozymes Involved in Metabolic Activation of Prodrugs. Molecules 2008, 13, 412-431.
Hosokawa M. Structure and Catalytic Properties of Carboxylesterase Isozymes Involved in Metabolic Activation of Prodrugs. Molecules. 2008; 13(2):412-431.Chicago/Turabian Style
Hosokawa, Masakiyo. 2008. "Structure and Catalytic Properties of Carboxylesterase Isozymes Involved in Metabolic Activation of Prodrugs." Molecules 13, no. 2: 412-431.