A structural examination of agrochemical processing by human carboxylesterase 1

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  • Hemmert Andrew C.
    Departments of Biochemistry and Biophysics, University of North Carolina
  • Redinbo Matthew R.
    Departments of Biochemistry and Biophysics, University of North Carolina Departments of Chemistry, University of North Carolina

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Human carboxylesterase 1 (hCE1) is the primary carboxylesterase expressed in the liver. This critical member of the phase I drug metabolism pathway detoxifies a wide-range of endobiotics, xenobiotics, and agrochemicals. To date, more than a dozen X-ray crystal structures have been elucidated of hCE1 in complex with a broad spectrum of ligands, including organophosphates. These structures provide valuable insights into agrochemical binding and metabolism by hCE1. For example, variable binding pockets that frame the enzyme's catalytic triad and a long, flexible loop capping this region appear to regulate substrate affinity. Stereoisomers of organophosphates illustrate the substrate selectivity of these two pockets. In contrast, pyrethroid isomers likely impact the positioning of the oxyanion hole required to stabilize the negatively charged transition-state oxygen. Finally, it appears that rates of spontaneous hCE1 reactivation in the presence of organophosphates are significantly affected by alkoxy placement within the active site.

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