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

Nature Structural Biology volume 10, pages 349356 (2003) | Download Citation

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  • A Corrigendum to this article was published on 01 July 2003

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.

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Acknowledgements

We thank G. Pielak, L. Spremulli, B. Bernstein and C. Kuhn for critical comments on the manuscript; P. Kuhn and J. Chrzas for help with data collection; D. Erie for access to AFM equipment; and members of the Redinbo Laboratory, including J. Chrencik, E. Howard-Williams, T. Lesher, S. Sakai and R. Watkins, for discussions and experimental assistance. The reseach was supported by the N.I.H. and a Burroughs Wellcome Career Award in the Biomedical Sciences (M.R.R), and by the N.I.H. (including a Core Grant) and the American Lebanese Syrian Associated Charities (P.M.P.).

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Affiliations

  1. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

    • Sompop Bencharit
    • , Yu Xue
    •  & Matthew R. Redinbo
  2. School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

    • Sompop Bencharit
  3. Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

    • Christopher L. Morton
    •  & Philip M. Potter
  4. Department of Biochemistry & Biophysics and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • Matthew R. Redinbo

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The authors declare no competing financial interests.

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Correspondence to Matthew R. Redinbo.

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DOI

https://doi.org/10.1038/nsb919

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