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Originally published In Press as doi:10.1074/jbc.M212210200 on January 7, 2003

J. Biol. Chem., Vol. 278, Issue 14, 12214-12221, April 4, 2003
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The 1.92-Å Structure of Streptomyces coelicolor A3(2) CYP154C1
A NEW MONOOXYGENASE THAT FUNCTIONALIZES MACROLIDE RING SYSTEMS*

Larissa M. PodustDagger §, Youngchang Kim, Miharu AraseDagger , Benjamin A. NeelyDagger , Brian J. Beck||, Horacio Bach||, David H. Sherman||, David C. Lamb**, Steven L. Kelly**, and Michael R. WatermanDagger

From the Dagger  Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, the  Argonne National Laboratory, Structural Biology Center, Argonne, Illinois 60439, the || Department of Microbiology and BioTechnology Institute, University of Minnesota, Minneapolis, Minnesota 55455, and the ** Wolfson Laboratory of P-450 Biodiversity, Institute of Biological Sciences, University of Wales Aberystwyth, Aberystwyth, Wales SY23 3DA, United Kingdom

Evolutionary links between cytochrome P450 monooxygenases, a superfamily of extraordinarily divergent heme-thiolate proteins catalyzing a wide array of NADPH/NADH- and O2-dependent reactions, are becoming better understood because of availability of an increasing number of fully sequenced genomes. Among other reactions, P450s catalyze the site-specific oxidation of the precursors to macrolide antibiotics in the genus Streptomyces introducing regiochemical diversity into the macrolide ring system, thereby significantly increasing antibiotic activity. Developing effective uses for Streptomyces enzymes in biosynthetic processes and bioremediation requires identification and engineering of additional monooxygenases with activities toward a diverse array of small molecules. To elucidate the molecular basis for substrate specificity of oxidative enzymes toward macrolide antibiotics, the x-ray structure of CYP154C1 from Streptomyces coelicolor A3(2) was determined (Protein Data Bank code 1GWI). Relocation of certain common P450 secondary structure elements, along with a novel structural feature involving an additional beta -strand transforming the five-stranded beta -sheet into a six-stranded variant, creates an open cleft-shaped substrate-binding site between the two P450 domains. High sequence similarity to macrolide monooxygenases from other microbial species translates into catalytic activity of CYP154C1 toward both 12- and 14-membered ring macrolactones in vitro.

* This work was supported by National Institutes of Health Grants GM37942 and ES00267 (to M. R. W.), P30 ES00267 (to L. M. P.), GM48562 (to D. H. S.), by Biotechnology and Biological Sciences Research Council and a Welcome Trust Grant (to S. L. K. and D. C. L.), and by NCI Cancer Biology Training Grant CA09138 (to B. J. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and the structure factors (code 1GWI) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

§ To whom correspondence should be addressed: Dept. of Biochemistry, Vanderbilt University, 23rd South at Pierce, Nashville, TN 37232-0146. Tel.: 615-343-4644; Fax: 615-322-4349; E-mail: larissa.m.podust@vanderbilt.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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