title: Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme.
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.
authors.affiliation: Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Sompop
authors.initials: S
authors.lastname: Bencharit
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: Yu
authors.initials: Y
authors.lastname: Xue
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Redinbo
mesh_terms: D001665:Binding Sites; D001711:Biotransformation; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D003042:Cocaine / Q000737:chemistry* / Q000493:pharmacokinetics*; D018360:Crystallography, X-Ray; D003932:Heroin / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009270:Naloxone / Q000737:chemistry / Q000493:pharmacokinetics; D009294:Narcotics / Q000737:chemistry / Q000493:pharmacokinetics; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013379:Substrate Specificity
chemical_list: D009294:Narcotics; D009270:Naloxone; D003932:Heroin; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D043182:Carboxylesterase; D003042:Cocaine