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Optical detection of cytochrome P450 by sensitizer-linked substrates

Dmochowski, Ivan J. and Crane, Brian R. and Wilker, Jonathan J. and Winkler, Jay R. and Gray, Harry B. (1999) Optical detection of cytochrome P450 by sensitizer-linked substrates. Proceedings of the National Academy of Sciences of the United States of America, 96 (23). pp. 12987-12990. ISSN 0027-8424. PMCID PMC23886.

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The ability to detect, characterize, and manipulate specific biomolecules in complex media is critical for understanding metabolic processes. Particularly important targets are oxygenases (cytochromes P450) involved in drug metabolism and many disease states, including liver and kidney dysfunction, neurological disorders, and cancer. We have found that Ru photosensitizers linked to P450 substrates specifically recognize submicromolar cytochrome P450cam in the presence of other heme proteins. In the P450:Ru-substrate conjugates, energy transfer to the heme dramatically accelerates the Ru-luminescence decay. The crystal structure of a P450cam:Ru-adamantyl complex reveals access to the active center via a channel whose depth (Ru-Fe distance is 21 Å) is virtually the same as that extracted from an analysis of the energy-transfer kinetics. Suitably constructed libraries of sensitizer-linked substrates could be employed to probe the steric and electronic properties of buried active sites.

Item Type:Article
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URLURL TypeDescription CentralArticle
Winkler, Jay R.0000-0002-4453-9716
Gray, Harry B.0000-0002-7937-7876
Additional Information:© 1999 by The National Academy of Sciences Contributed by Harry B. Gray, September 14, 1999. We thank A. M. Bilwes for assistance with protein expression and crystallization, D. C. Rees for use of facilities and comments, S. G. Sligar for providing a P450cam vector, J. H. Dawson for several discussions, M. Machczynski for computational assistance, and the Stanford Synchrotron Research Laboratory for use of data collection facilities. I.J.D. is a National Institutes of Health predoctoral trainee (Grant GM08346). B.R.C. is a Helen Hay Whitney Postdoctoral Fellow. This work was supported by National Science Foundation Grant CHE9807150. Data deposition: The atomic coordinates of the P450:Ru-C9-Ad structure have been deposited in the Protein Data Bank, (PDB ID code 1qmq). The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Funding AgencyGrant Number
NIH Predoctoral FellowshipGM08346
Helen Hay Whitney FoundationUNSPECIFIED
Issue or Number:23
PubMed Central ID:PMC23886
Record Number:CaltechAUTHORS:DMOpnas99
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:733
Deposited By: Archive Administrator
Deposited On:21 Sep 2005
Last Modified:22 Nov 2019 09:58

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