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OtherShort Communication

Identification of Binding Sites of Non-I-Helix Water Molecules in Mammalian Cytochromes P450

Charles W. Locuson and Timothy S. Tracy
Drug Metabolism and Disposition December 2006, 34 (12) 1954-1957; DOI: https://doi.org/10.1124/dmd.106.011890
Charles W. Locuson
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Timothy S. Tracy
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Abstract

The cytochromes P450 (P450s) enzymes are integral in determining the disposition of many therapeutic compounds. At the molecular level, the details of P450 catalysis are still under investigation, but the importance of water-mediated proton shuttles seems evident in the catalytic cycle as it progresses through various heme iron-oxygen enzyme intermediates. The study of P450-bound waters has been largely restricted to bacterial enzymes that may or may not reflect the location or function of waters in human drug-metabolizing P450s. However, in recent years, 16 structures of mammalian P450s containing crystallographic waters have been deposited in the Protein Data Bank. Described herein is the identification of seven well defined water clusters in mammalian P450s identified by calculating the density of globally aligned waters as reported by Tanner and coworkers [Bottoms CA, White TA, and Tanner JJ (2006) Proteins 64:404–421 (DOI: 10.1002/prot.21014)]. All water binding sites were in or within the immediate vicinity of the active sites of the P450s, but most were not near the conserved I-helix threonine often implicated in P450 catalysis. Therefore, it is possible that some of the water binding sites identified here ultimately determine P450 catalytic efficiency either by working as an extension of the I-helix water network, or by acting in novel proton shuttles that modulate the nonproductive shunting of reactive oxygen species.

Footnotes

  • Financial support from National Institutes of Health Grant GM063215 is gratefully acknowledged.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.011890.

  • ABBREVIATIONS: P450, cytochrome P450; rmsd, root mean square deviation; pdb, Protein Data Bank.

    • Received July 7, 2006.
    • Accepted August 29, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (12)
Drug Metabolism and Disposition
Vol. 34, Issue 12
1 Dec 2006
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OtherShort Communication

Identification of Binding Sites of Non-I-Helix Water Molecules in Mammalian Cytochromes P450

Charles W. Locuson and Timothy S. Tracy
Drug Metabolism and Disposition December 1, 2006, 34 (12) 1954-1957; DOI: https://doi.org/10.1124/dmd.106.011890

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OtherShort Communication

Identification of Binding Sites of Non-I-Helix Water Molecules in Mammalian Cytochromes P450

Charles W. Locuson and Timothy S. Tracy
Drug Metabolism and Disposition December 1, 2006, 34 (12) 1954-1957; DOI: https://doi.org/10.1124/dmd.106.011890
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