Structural Insights into Drug Processing by Human Carboxylesterase 1: Tamoxifen, Mevastatin, and Inhibition by Benzil

Journal Article · Mon Jul 19 04:00:00 EDT 2010 · J. Mol. Biol.

OSTI ID:1008561

Fleming, Christopher D; Bencharit, Sompop; Edwards, Carol C; Hyatt, Janice L; Tsurkan, Lyudmila; Bai, Feng; Fraga, Charles; Morton, Christopher L; Howard-Williams, Escher L; Potter, Philip M; Redinbo, Matthew R ^[1]

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1. UNC

Human carboxylesterase 1 (hCE1) exhibits broad substrate specificity and is involved in xenobiotic processing and endobiotic metabolism. We present and analyze crystal structures of hCE1 in complexes with the cholesterol-lowering drug mevastatin, the breast cancer drug tamoxifen, the fatty acyl ethyl ester (FAEE) analogue ethyl acetate, and the novel hCE1 inhibitor benzil. We find that mevastatin does not appear to be a substrate for hCE1, and instead acts as a partially non-competitive inhibitor of the enzyme. Similarly, we show that tamoxifen is a low micromolar, partially non-competitive inhibitor of hCE1. Further, we describe the structural basis for the inhibition of hCE1 by the nanomolar-affinity dione benzil, which acts by forming both covalent and non-covalent complexes with the enzyme. Our results provide detailed insights into the catalytic and non-catalytic processing of small molecules by hCE1, and suggest that the efficacy of clinical drugs may be modulated by targeted hCE1 inhibitors.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1008561
• Journal Information: J. Mol. Biol., Journal Name: J. Mol. Biol. Journal Issue: (1) ; 2005 Vol. 352; ISSN JMOBAK; ISSN 0022-2836
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
CARBOXYLESTERASES
CRYSTAL STRUCTURE
CRYSTALLOGRAPHY
DESIGN
ESTERS
MAMMARY GLANDS
METABOLISM
NEOPLASMS
PROCESSING
PROTEIN STRUCTURE
SPECIFICITY
SUBSTRATES
TAMOXIFEN
XENOBIOTICS