Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme.

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Bencharit S, Morton CL, Xue Y, Potter PM, Redinbo MR

Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme.

Nat Struct Biol. 2003 May;10(5):349-56.

PubMed ID

12679808 [ View in PubMed

]

Abstract

We present the first crystal structures of a human protein bound to analogs of cocaine and heroin. Human carboxylesterase 1 (hCE1) is a broad-spectrum bioscavenger that catalyzes the hydrolysis of heroin and cocaine, and the detoxification of organophosphate chemical weapons, such as sarin, soman and tabun. Crystal structures of the hCE1 glycoprotein in complex with the cocaine analog homatropine and the heroin analog naloxone provide explicit details about narcotic metabolism in humans. The hCE1 active site contains both specific and promiscuous compartments, which enable the enzyme to act on structurally distinct chemicals. A selective surface ligand-binding site regulates the trimer-hexamer equilibrium of hCE1 and allows each hCE1 monomer to bind two narcotic molecules simultaneously. The bioscavenger properties of hCE1 can likely be used to treat both narcotic overdose and chemical weapon exposure.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Naloxone	Liver carboxylesterase 1	Protein	Humans	Unknown	Binder	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Homatropine	Liver carboxylesterase 1	Protein	Humans	Unknown	Substrate	Details

Polypeptides

Name	UniProt ID
Liver carboxylesterase 1	P23141	Details