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    Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine†

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    Issue Date
    2012-05
    Author
    DeVore, Natasha M.
    Meneely, Kathleen M.
    Bart, Aaron G.
    Stephens, Eva Susanne
    Battaile, Kevin P.
    Scott, Emily E.
    Publisher
    Wiley
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
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    Abstract
    Human xenobiotic-metabolizing cytochrome P450 (P450) enzymes can each bind and monooxygenate a diverse set of substrates, including drugs, often producing a variety of metabolites. Additionally a single ligand can interact with multiple cytochrome P450 enzymes, but often the protein structural similarities and differences that mediate such overlapping selectivity are not well understood. Even though the P450 superfamily has a highly canonical global protein fold, there are large variations in the active site size, topology, and conformational flexibility. We have determined how a related set of three human cytochrome P450 enzymes bind and interact with a common inhibitor, the muscarinic receptor agonist drug pilocarpine. Pilocarpine binds and inhibits the hepatic CYP2A6 and respiratory CYP2A13 enzymes much more efficiently than the hepatic CYP2E1 enzyme. To elucidate key amino acids involved in pilocarpine binding, crystal structures of CYP2A6 (2.4 Å), CYP2A13 (3.0 Å), CYP2E1 (2.35 Å), and a CYP2A6 mutant enzyme, CYP2A6 I208S/I300F/G301A/S369G (2.1 Å), have been determined with pilocarpine in the active site. In all four structures, pilocarpine coordinates to the heme iron, but comparisons reveal how individual amino acids lining the active sites of these three distinct human enzymes interact differently with the inhibitor pilocarpine. HYPERLINKING TO DATABASES: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/) with the following codes: CYP2A6 with pilocarpine (3T3R), CYP2A6 I208S/I300F/G301A/S369G with pilocarpine (3T3Q), CYP2A13 with pilocarpine (3T3S), and CYP2E1 with pilocarpine (3T3Z).
    Description
    This is the peer reviewed version of the following article: DeVore, N. M., Meneely, K. M., Bart, A. G., Stephens, E. S., Battaile, K. P. and Scott, E. E. (2012), Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine. FEBS Journal, 279: 1621–1631. doi:10.1111/j.1742-4658.2011.08412.x, which has been published in final form at http://doi.org/10.1111/j.1742-4658.2011.08412.x. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
    URI
    http://hdl.handle.net/1808/24476
    DOI
    https://doi.org/10.1111/j.1742-4658.2011.08412.x
    Collections
    • Medicinal Chemistry Scholarly Works [225]
    Citation
    DeVore, N. M., Meneely, K. M., Bart, A. G., Stephens, E. S., Battaile, K. P. and Scott, E. E. (2012), Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine. FEBS Journal, 279: 1621–1631. doi:10.1111/j.1742-4658.2011.08412.x

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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