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Molecules. 2008 Feb 18;13(2):412-31.

Structure and catalytic properties of carboxylesterase isozymes involved in metabolic activation of prodrugs.

Author information

1
Laboratory of Drug Metabolism and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Shiomi-Cho, Choshi-City, Chiba 288-0025, Japan. Masakiyo@cis.ac.jp

Abstract

Mammalian carboxylesterases (CESs) comprise a multigene family whose gene products play important roles in biotransformation of ester- or amide-type prodrugs. They are members of an alpha,beta-hydrolase-fold family and are found in various mammals. It has been suggested 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 have been identified belong to the CES1 or CES2 family. The substrate specificities of CES1 and CES2 are significantly different. The CES1 isozyme mainly hydrolyzes a substrate with as mall alcohol group and large acyl group, but its wide active pocket sometimes allows it to act 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 conjugate formation due to the presence of conformational interference in the active pocket. Since pharmacokinetic and pharmacological data for prodrugs obtained from preclinical experiments using various animals are generally used as references for human studies, it is important to clarify the biochemical properties of CES isozymes. Further experimentation for an understanding of detailed substrate specificity of prodrugs for CES isozymes and its hydrolysates will help us to design the ideal prodrugs.

PMID:
18305428
PMCID:
PMC6245361
DOI:
10.3390/molecules13020412
[Indexed for MEDLINE]
Free PMC Article

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