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HERO ID
6545357
Reference Type
Journal Article
Title
Human carboxylesterase 1: from drug metabolism to drug discovery
Author(s)
Redinbo, MR; Bencharit, S; Potter, PM
Year
2003
Is Peer Reviewed?
Yes
Journal
Biochemical Society Transactions
ISSN:
0300-5127
EISSN:
1470-8752
Volume
31
Issue
Pt 3
Page Numbers
620-624
Language
English
PMID
12773168
DOI
10.1042/BST0310620
Web of Science Id
WOS:000183622500028
Abstract
Human carboxylesterase 1 (hCE1) is a serine esterase involved in both drug metabolism and activation, as well as other biological processes. hCE1 catalyses the hydrolysis of heroin and cocaine, and the transesterification of cocaine in the presence of ethanol to the toxic metabolite cocaethylene. We have determined the crystal structures of hCE1 in complex with either the cocaine analogue homatropine or the heroin analogue naloxone. These are the first structures of a human carboxylesterase, and they provide details about narcotic metabolism in humans. hCE1's active site contains rigid and flexible pockets, explaining the enzyme's ability to act both specifically and promiscuously. hCE1 has also been reported to contain cholesteryl ester hydrolase, fatty acyl-CoA hydrolase and acyl-CoA:cholesterol acyltransferase activities, and thus appears to be involved in cholesterol metabolism. Since the enzyme may be useful as a treatment for cocaine overdose, and may afford protection against chemical weapons like Sarin, Soman and VX gas, hCE1 could serve as both a drug and a drug target. Selective hCE1 inhibitors targeted to several sites on the enzyme may also pave the way for novel clinical tools to manage cholesterol homoeostasis in humans.
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