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SHORT COMMUNICATION

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

Department of Experimental and Clinical Pharmacology, University of Minnesota, College of Pharmacy, 5-130 Weaver-Densford Hall, 308 Harvard Street SE, Minneapolis, Minnesota

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.